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					                           NHMRC Research Achievements - SUMMARY
                           END OF GRANT REPORTS
                 OUTCOMES OF NHMRC FUNDED RESEARCH INTO
        ARTHRITIS, OSTEOPOROSIS AND OTHER MUSCULOSKELETAL DISORDERS
                              ENDING 2000 TO 2009
                                  CONTENTS

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 Australian National University                            University of Adelaide
 Baker IDI Heart and Diabetes Institute                    University of Canberra
 Curtin University of Technology                           University of Melbourne
 Deakin University                                         University of New South Wales
 Flinders University                                       University of Queensland
 Garvan Institute of Medical Research                      University of Sydney
 Griffith University                                       University of Tasmania
 Institute of Medical and Veterinary Science               University of Western Australia
 Macfarlane Burnet Institute for Medical Research
 and Public Health                                         University of Wollongong
 Monash University                                         Victoria University
 Murdoch Childrens Research Institute                      Walter and Eliza Hall Institute
 Queensland University of Technology                       Walter and Eliza Hall Institute
 Royal Melbourne Institute of Technology                   Walter and Eliza Hall Institute
 Sir Charles Gairdner Hospital                             Walter and Eliza Hall Institute
 St. Vincent's Institute of Medical Research               Walter and Eliza Hall Institute
                            NHMRC Research Achievements - SUMMARY
Australian National University


Grant ID:      366771                                           Start Year:      2006
CIA Name:      Prof Christopher C Goodnow                       End Year:        2006
Main RFCD:     Humoral Immunology and Immunochemistry           Total funding:   $191,250.00
Admin Inst:    Australian National University                   Grant Type:      Standard Project Grant


Title of research award: Mechanisms controlling antibody production by modulating B cell antigen receptor
signaling

Lay Description (from application):

This project will analyse mechanisms that regulate antibody production in health and disease. In health, antibodies
are normally made exclusively against infectious agents, providing long-lasting immunity. Unknown errors in the
control of antibody production result in autoimmune diseases such as systemic lupus or rheumatoid arthritis,
where antibodies are made against parts of our own bodies, or result in allergies where antibodies are made
against innocuous elements of our environment, or result in uncontrolled B cell accumulation in lymphoma,
leukemia and myeloma. In order to develop rational, specific methods for treating these diseases, it is necessary to
identify and understand the biochemical mechanisms that normally control antibody formation against infectious
agents, self components, and innocuous environmental agents. The project focuses on defining the biochemical
mechanisms by which the antibody-forming cells, B lymphocytes, sense infectious, innocuous, or self
components. These cells carry specific receptors that bind these components and transmit signals into the B
lymphocyte. The research will determine how different types of signal are transmitted by the receptor so that,
normally, large amounts of antibody are made against infectious agents but very little antibody is made against
self components, and that B cell accumulation is tightly limited. By identifying how the types of signals are
changed, the results of this project will reveal control mechanisms that may be altered in autoimmunity, allergy,
immune deficiency, or lymphoma, and that may be able to be used as drug targets to cure these diseases.

Research achievements (from final report):

The study identified how the immune system's antibody-forming cells, B lymphocytes, diminish their capacity to
multiply and make antibody if this antibody reacts with parts of our own body, or enhance their capacity to
multiply and make antibody if this antibody has previously been proven to react with a foreign microbe. The study
provides fundamental insights into two central questions in all of immunology: how forbidden clones of self-
reactive cells are silenced, and how desired clones of microbe-fighting cells are able to make a greater and more
rapid response upon a second exposure to the same microbe. The results thus provide a mechanistic understanding
for future research to prevent and treat autoimmune diseases and to enhance the effectiveness and longevity of
immunization against infection.

Expected future outcomes:

We are continuing to define the components of the gene program that inactivates forbidden clones of B cells,
testing the function of key elements of the program and how they are altered by subtle inherited differences, and
expect to submit further high impact publications on this during 2009.

Name of contact:      Chris Goodnow
Email of contact:     Chris.Goodnow@anu.edu.au
                            NHMRC Research Achievements - SUMMARY


Baker IDI Heart and Diabetes Institute

Grant ID:      317840                                            Start Year:       2005
CIA Name:      Dr Anita E Wluka                                  End Year:         2008
Main RFCD:     Epidemiology                                      Total funding:    $324,000.00
Admin Inst:    Baker IDI Heart and Diabetes Institute            Grant Type:       Public Health (Australia)
                                                                 Fellowship


Title of research award: Identification of lifestyle factors which act as determinants of articular knee cartilage
loss

Lay Description (from application):

No available Lay Description

Research achievements (from final report):

This award has enhanced our understanding of structures within the knee, and how they differ in those with and
without knee osteoarthritis. It has added to our understanding of how lifestyle and biomechanical factors affect the
knee in healthy people, which may provide insight into the mechanism of risk factors for knee osteoarthritis. For
example, body fat mass was shown to be detrimental to the amount of knee cartilage present. It may be that for
effective prevention of knee OA, weight reduction strategies should include muscle maintenance: simple weight
loss alone may be insufficient. Thus, these may facilitate more effective strategies to prevent knee osteoarthritis in
the future.

Expected future outcomes:

Extension of this work may provide a stronger basis to enable intervention studies to be performed to reduce the
risk of knee osteoarthritis.

Name of contact:       Anita Wluka
Email of contact:      anita.wluka@med.monash.edu.au
                            NHMRC Research Achievements - SUMMARY

Curtin University of Technology

Grant ID:       111110                                            Start Year:       2000
CIA Name: Dr Deborah A Kerr                                       End Year:         2000
Main RFCD: Clinical Chemistry                                     Total funding: $43,574.00
Admin Inst: Curtin University of Technology                       Grant Type: New Investigator
Title of research award: The effects of a two year randomised exercise intervention on markers of bone turnover
in postmenopausal women
Lay Description (from application):
Osteoporosis is a condition where the bones become more fragile and can break more easily. In Australia after age
60, three out of every five women and three out of every ten men will fracture a bone. When people fracture a hip
they lose their independence and become much less mobile. Exercise is one lifestyle approach which may help in
preventing osteoporosis by slowing bone loss and keeping the muscles strong. Previous research has not been able
to clearly demonstrate the usefulness of exercise due partly to the difficulty in getting people to exercise for a least
one year, which is how long bone studies must be carried out for. We have conducted two large research studies in
women past the menopause where they have done weight training exercises. In the previous study we showed the
greatest increase in bone mass occurred in those women lifting the heaviest weights. In a recently completed two
year study in 126 woman, which forms the basis of this proposal, we found a weight training program was
effective at increasing the bone mass at the hip, a common fracture site. The fitness group did not show any
increase. So although we have been able to show this type of exercise helps increase bone mass we don't know
how the bone is able to respond to this. The question we wish to address with this proposal is does exercise slow
the breakdown of bone or does it help form new bone? The best way to be able to answer this question is by
measuring certain products in blood, known as bone markers. Bone is continually turning overthese markers are
released from bone into the blood. By studying these bone markers in blood samples taken from the subjects over
two years it will helps us determine how exercise is affecting bone. From our previous studies we know that
weight training can help slow bone loss. By measuring the bone markers we will then be able to make
recommendations to people on how exercise will help prevent bone loss.
Research achievements (from final report):
The evidence for the biochemical response to exercise comes from cross-sectional data and a limited number of
longitudinal studies. There have been a small number of studies examining the effect of exercise on bone turnover.
No study to date has examined the biochemical response to exercise over a two yaer strength training regime. The
aim of this study was to investigate the effects of a two year randomised exercise intervention on the biochemical
markers of bone turnover in postmenopausal women. The subjects consisted of 126 women who were more than
four years past the menopause and physically capable of exercising. Assignment was by block randomisation to
one of three groups: a strength, circuit or non-exercise control. All subjects were given 600 mg of elemental
calcium daily. The strength group protocol emphasized skeletal loading wheras the circuit group emphasized
aerobic fitness and both exercise groups attended three supervised exercise sessions per week. There was a
significant difference between the groups for changes in total hip BMD (Kerr et al. JBMR 2001) but there was no
significant difference between the groups for changes in serum and urine markers measured. Vitamin D showed
alternating changes which may be due to seasonal effects. The lack of effect observed with the bone markers may
reflect the timing of the sampling. As blood sampling occurred at six monthly intervals, earlier sampling (at
monthly intervals in the first six months) may have been able to detect changes in the bone turnover markers.
Alternatively the measurement error in the bone markers may have been too large to detect changes. The CV error
was 6% for bone-specific alkaline phosphatase and 7% for urine total deoxypridinoline. The lack of effect
observed suggests that exercise interventions need to measure bone markers in the early stages of the exercise
intervention. This may be important in understanding the mechanism by which exercise may act on bone
remodeling.
Expected future outcomes:
The outcome of this study indicates the need for further research to examine the exercise effects on biochemical
markers of bone turnover. We still have little understanding of the mechanism by which exercise acts on bone.
This is important so that more concrete public health recommendations can be made on the potential benefits of
exercise in preventing osteoporosis.

Name of contact:       Dr Deborah Kerr
Email of contact:      d.kerr@curtin.edu.au
                           NHMRC Research Achievements - SUMMARY
Deakin University

Grant ID:      136928                                         Start Year:        2001
CIA Name:      Dr Robin M Daly                                End Year:          2004
Main RFCD:     Medical and Health Sciences not elsewhere classified              Total funding: $223,268.00
Admin Inst:    Deakin University                              Grant Type:        Public Health (Australia)
                                                              Fellowship


Title of research award: Does increased dietary calcium-vitamin D and exercise increase bone density in older
men

Lay Description (from application):

No available Lay Description

Research achievements (from final report):

Osteoporosis is recognised as an increasing public health problem in men. This highlights the importance of
identifying lifestyle interventions that are effective at maintaining bone strength in men. In a 2 year randomised
study involving 167 men aged over 50, we found that supplementing the diet with reduced fat calcium-vitamin D3
enriched milk was effective for stopping or slowing the rate of bone loss at several clinically important skeletal
sites. Since milk is one of the most natural, convenient and readily absorbed sources of calcium, fortifying milk
with calcium and vitamin D may represent a simple, nutritionally sound and cost effective approach to reduce the
health and economic burden of osteoporosis in men. The second objective of this program of research was to
examine whether calcium-vitamin D3 fortified milk enhances the effects of exercise on bone strength in older
men. This study is currently in progress; 182 men have been randomly allocated to one of four groups: 1)
exercise+calcium-vitamin D3; 2) exercise alone; 3) calcium-vitamin D3 alone, or 4) a control group. As part of
this trial, we developed an exercise algorithm to aid decision making for exercise prescription for health care
professional in the prevention and management of osteoporosis. This algorithm is unique because it takes into
account an individuals level of fracture risk based on their bone density and functional/clinical risk status.
Together, the findings from this work will provide the evidential basis for health care professionals to make sound
decisions with regard to exercise and diet for the prevention and management of osteoporosis in older adults,
particularly men.

Expected future outcomes:

The findings from this program of research will provide the evidence base on which to develop physical activity
and nutrition guidelines and public health policy to promote improve musculoskeletal health in older adults,
particularly men.

Name of contact:      Dr Robin Daly
Email of contact:     robin.daly@deakin.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      229312                                             Start Year:       2003
CIA Name:      Prof Shona Bass                                    End Year:         2006
Main RFCD:     Endocrinology                                      Total funding:    $180,000.00
Admin Inst:    Deakin University                                  Grant Type:       Standard Project Grant

Title of research award: The effect of exercise on the size and shape of cortical bone during different stages of
maturation in males and females
Lay Description (from application):
Osteoporosis is a condition in which the skeleton becomes fragile and susceptible to fractures. It is a public health
problem that affects both men and women over the age of sixty. Although osteoporosis affects the elderly, the
most opportune time to prevent osteoporosis may be during childhood. Physical activity is a lifestyle factor known
to affect the strength of the skeleton. Bone density is commonly used as a measure of bone strength because it is
easily measured and is related to the breaking strength of bones. However changes in the shape of bones can also
affect bone strength with or without an increase in bone density. Changes in bone shape in response to exercise in
children or adults have rarely been investigated, and little is known about the effects of exercise on bone shape
during different stages of growth. This study is the first to investigate how exercise during childhood may affect
bone strength by changing bone shape. 45 elite female tennis players aged between 6 to 18 years have completed
two years of this study. 90 novice and competitive male tennis players aged between 6 to 20 years and 60 healthy
age matched controls will be asked to participate in this study. Measurements will be made annually for three
years. The bone shape and density of the dominant and non-dominant arms of the players will be compared with
the children who don't play tennis - comparisons will also be made between i) different stages of puberty and ii)
girls and boys. The findings of this study are important because the lifestyle of children today may predispose
them to a greater risk of osteoporosis late in life. Physical activity may be the most important modifiable
protective factor against fragile bones in old age. The findings of this study will be the first to provide insight into
whether there is a unique time during growth when exercise will result in the greatest increase in bone strength by
changing bone shape.

Research achievements (from final report):

The objective of this project was to investigate the effects of tennis playing (as a model of repetitive loading) on
bone strength in boys and girls during different stages of growth. The unique feature of the study was to use
magnetic resonance imaging to obtain cross sections of the bone in order to describe how the growing bones
respond to repetitive mechanical stimuli. Measuring the effects of exercise was obtained by comparing the
dominant and nondominant arms of young tennis players. The preliminary results show that loading the skeleton
before puberty leads to a significant improvement in bone strength in boys and girls. The prepubertal skeleton has
the capacity to respond to loading by adding more mineral on the external surface of the bone, leading to a marked
increase in bone size and bone strength. Interestingly, boys seem to have a larger window of opportunity than girls
to optimize their bone strength through exercise: the benefits obtained before puberty in boys was further
enhanced in peri-puberty if training was maintained whereas it was not the case in girls. If confirmed by the
analysis of the longitudinal data, these results would have important implications for exercise recommendations to
improve bone strength during growth. Children, and particularly girls, should be encouraged to participate in
impact-loading exercise from prepuberty, in order to maximize their peak bone mass in early adulthood and
decrease their fracture risk throughout life.

Expected future outcomes:

The three-year data will provide valuable information on how much bone strength increases during growth, what
benefits can be obtained by participating in high-impact exercise and to what extent these benefits may differ
between boys and girls in terms of magnitude and timing. Exercise prescription for bone health could then be re-
designed according to maturity status and gender.

Name of contact:       Shona Bass
Email of contact:      shona.bass@deakin.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      229320                                            Start Year:      2003
CIA Name:      Prof Shona Bass                                   End Year:        2008
Main RFCD:     Preventive Medicine                               Total funding:   $415,000.00
Admin Inst:    Deakin University                                 Grant Type:      Population Health CDA


Title of research award: Promoting Physical Activity and Nutrition to Prevent Osteoperosis - A Lifespan
Approach

Lay Description (from application):

No available Lay Description

Research achievements (from final report):

The development of a healthy skeleton during the growing years has implications for adult skeletal health. This
research has used cutting edge technology (pQCT and MRI) to gain a greater insight into how the growing
skeleton responds to exercise and nutrition during different stages of maturation and in both genders. The results
show that even small amounts of regular exercise (20 minutes, 2 to 3 times per week) that involves 'impact'
(hopping, skipping and jumping) can lead to clinically important improvements in bone strength. In children who
have less than the recommended dietary intake of calcium the inclusion of calcium rich foods (dairy foods and
foods fortified with calcium) in their daily diet can also add to the benefit of exercise. The timing of when children
exercise to gain the optimal skeletal benefit appears in the few years before and early in adolescence. Preliminary
findings suggest that the window of opportunity to make the most of exercise to build a stronger skeleton most
efficiently may be shorter in girls than boys. These findings highlight the importance of children being involved in
osteogenic (bone building) exercise before and early in adolescence. Appropriate nutrition that provides enough
energy and protein for all body functions, exercise, as well as growth processes has been shown to be very
important for optimal bone health. This research has shown that poor bone health can result from inadequate
nutrition due to delayed maturation, menstrual dysfunction (in girls) and reduced growth in height.

Expected future outcomes:

Future outcomes from this work will include: defining the prescription of exercise that provides the optimal
stimulus for building stronger bones in children that will lead to long term adult bone health and a better
understanding of the effects of inadequate energy intakes on bone health and growth.

Name of contact:       Dr Gaele Ducher
Email of contact:      gaele.ducher@deakin.edu.au
                             NHMRC Research Achievements - SUMMARY
Flinders University

Grant ID:      160062                                              Start Year:       2001
CIA Name:      Prof Jegan Krishnan                                 End Year:         2003
Main RFCD:     Orthopaedics                                        Total funding:    $187,000.00
Admin Inst:    Flinders University                                 Grant Type:       Standard Project Grant


Title of research award: The design, development and clinical asssessment of a new metacarpophalangeal joint
prosthesis.

Lay Description (from application):

Rheumatoid arthritis is a crippling form of arthritis that affects many people in the community. It commonly
involves the finger joints in the hands resulting in deformity, pain and subsequent loss of function. There have
been implants designed for finger joint replacement, but unfortunately these implants have had only moderate
benefits and can break and lead to further joint destruction resulting in the worsening of deformity and pain. A
new implant for finger joint replacement has been developed. This implant has several potential advantages.
Firstly the unique design acts to prevent recurring deformity in the fingers with rheumatoid disease while allowing
functional motion. Secondly, it is thought that patients will return to function earlier and avoid the need for further
finger surgery as this implant design relies less on the tissues around it for stability. The purpose of this study is to
investigate the biomechanical and clinical benefits of this new implant for finger joint replacement. The new
design will undergo specific laboratory tests and be used in a clinical trial to quantify the therapeutic benefits it
provides to patients with rheumatoid arthritis.

Research achievements (from final report):

The reseach in the project assessed a newly developed implant for knuckle joint replacement. This joint was tested
biomechanically and manufacturing processes and the materials used to make the implant were refined
accordingly. Subsequent implant of this new joint into a person with rheumatoid arthritis showed that the joint was
effective in restoring function to the hand. One very important observation from this research was that the tools
available to assess hand function were limited, particularly for people with rheumatoid arthritis before and after
joint-replacement surgery. Therefore, considerable effort was made to improve and standardise the available tools
and to develop new and more appropriate tools and measurement devices.

Expected future outcomes:

Commercial development of the newly developed prosthesis is continuing with an Orthopaedic prosthesis
manufacturer. The development and assessment of hand-function testing tools and devices is also expected to lead
to new instruments more appropriate to the rheumatoid hand.

Name of contact:       Professor Jegan Krishnan
Email of contact:      jegan.krishnan@flinders.edu.au
                             NHMRC Research Achievements - SUMMARY

Grant ID:       275547                                              Start Year:       2004
CIA Name:       Prof Malcolm D Smith                                End Year:         2006
Main RFCD:      Rheumatology and Arthritis                          Total funding:    $252,375.00
Admin Inst:     Flinders University                                 Grant Type:       Standard Project Grant


Title of research award: Predictors of the outcomes for joint inflammation and damage in recent onset
rheumatoid arthritis patients

Lay Description (from application):

Currently, it is difficult to predict what will happen to an individual patient who presents with newly diagnosed
rheumatoid arthritis, either as a result of the natural history of the disease or as a result of drug treatment. It is also
difficult to decide which drug treatment to offer a patient and when to decide to change the treatment to obtain a
better clinical response. This study will investigate whether it is possible to predict the outcomes for a particular
patient with rheumatoid arthritis for joint inflammation and joint destruction, based on the findings in the joint
lining tissue. This study will also investigate whether it is possible to make decisions on the likely success of drug
treatment given to a patient with rheumatoid arthritis based on the initial or subsequent joint lining tissue biopsies.
If successful, this study will lead to a greater ability to advise patients about likely outcomes from their condition,
either with or without treatment and also to predict whether a treatment is likely to work at an early stage. In
addition, this study may identify future potential treatments for rheumatoid arthritis.

Research achievements (from final report):

We have identified a number of potential synovial tissue biomarkers for the clinical response to drug treatment in
rheumatoid arthritis in collaboration with several international research groups, which have been presented at
international meetings and resulted in 9 publications.

Expected future outcomes:

We have now developed further research projects to explore further these biomarkers and develop them for
clinical applications

Name of contact:        Professor Malcolm D Smith
Email of contact:       malcolm.smith@health.sa.gov.au
                            NHMRC Research Achievements - SUMMARY
Garvan Institute of Medical Research

Grant ID:      376001                                             Start Year:      2005
CIA Name:      Prof Charles R Mackay                              End Year:        2006
Main RFCD:     Immunology not elsewhere classified                Total funding:   $166,500.00
Admin Inst:    Garvan Institute of Medical Research               Grant Type:      Development Grant


Title of research award: A novel therapy to treat inflammatory disease

Lay Description (from application):

Complement factor C5a is one of the most potent inflammatory mediators in the body. We have developed a
monoclonal antibody that blocks the C5a receptor in vitro, and completely shuts down disease in a mouse model
of rheumatoid arthritis. We plan to develop this promising new antibody into a potent therapy to treat a range of
chronic and acute inflammatory diseases. The antibody has been humanised and this will be tested in three models
of inflammation (rheumatoid arthritis, sepsis and colitis) to determine the efficacy of the antibody, safety, the most
effective dose, timing and route of administration. These studies are a necessary prelude to human clinical trials,
which we hope to perform in approximately 24 months.

Research achievements (from final report):

We are developing a novel antibody-based drug for treatment of chronic and acute inflammatory diseases such as
rheumatoid arthritis, sepsis and ischaemia-reperfusion injury. The antibody targets the receptor C5aR, and blocks
binding and signalling by the potent pro-inflammatory molecule C5a. A humanised form of the antibody suitable
for human therapy has been produced and tested for effectiveness in an animal model of inflammatory arthritis.
We were able to completely block new inflammation and reverse established inflammation using the anti-C5aR
antibody. We showed that the antibody blocked influx of leukocytes (neutrophils, monocytes) into the joints of the
mice, and that it did this by blocking migration of the cells from the blood into the tissue. The antibody did not kill
the leukocytes. These studies provided important information for designing clinical trials. The antibody appears
safe and effective in animals, and if the same is shown in humans, the drug should provide a new option for
treating patients with chronic inflammatory disease, potentially alleviating the pain, suffering and reduced
functioning associated with such diseases.

Expected future outcomes:

The anti-C5aR antibody has been licensed by Novo Nordisk A/S, and is currently in preclinical development.
Clinical trials in chronic inflammatory diseases are planned over the next few years. If the treatement proves safe
and effective, a new anti-inflammatory therapy will become available.

Name of contact:       Prof Charles Mackay
Email of contact:      c.mackay@garvan.org.au
                           NHMRC Research Achievements - SUMMARY

Grant ID:     402725                                           Start Year:      2006
CIA Name:     Prof Jonathan Sprent                             End Year:        2006
Main RFCD:    Cellular Immunology                              Total funding:   $558,750.00
Admin Inst:   Garvan Institute of Medical Research             Grant Type:      Standard Project Grant


Title of research award: Immunoregulation of subsets of memory CD8+ T cells

Lay Description (from application):

Information will be sought on the properties of T cells, a class of white blood cells that play a vital role in
combating infectious agents. Using mouse models, subsets of T cells that carry immunological memory will be
studied and assessed for their rate of cell division and dependence on soluble messengers known as cytokines and
other stimuli. The data will provide useful knowledge on the causes of autoimmune diseases (such as rheumatoid
arthritis, type 1 diabetes and lupus) and help in the development of successful second generation vaccines.

Research achievements (from final report):

Signifiicnt progress was made in determining how immune cells are kept alive in the body through contact with
growth factors (cytokines) and other ligands in the microenvironment of the lymphoid tissues. Two papers have
been submitted on the role of particular cytokines, namely IL-7 and IL-15, in maintaining the survival and
function of the two main subsets of T cells, namely CD4 cell and CD8 cells. Information from these studies will
ultimately lead to the development of new treatments for autoimmune disease and immunodeficiency.

Expected future outcomes:

Continuing studies on the factors controlling the survival and function of T cells and other immune cells will
inevitably lead to improved methods for vaccine design and treatment of various disease of the immune system.

Name of contact:      Jonathan Sprent
Email of contact:     j.sprent@garvan.org.au
                           NHMRC Research Achievements - SUMMARY

Grant ID:     183700                                           Start Year:      2002
CIA Name:     Prof Charles R Mackay                            End Year:        2007
Main RFCD:    Cellular Immunology                              Total funding:   $0.00
Admin Inst:   Garvan Institute of Medical Research             Grant Type:      New Program Grant


Title of research award: Cellular and Molecular Studies of the Adaptive Immune Response in Health and
Disease

Lay Description (from application):

No available Lay Description

Research achievements (from final report):

Research was focused on pinpointing the reason why 5% of the population is susceptible to autoimmune and
inflammatory diseases (eg Lupus, Rheumatoid Arthritis (RA), Inflammatory Bowel Disease, Multiple Sclerosis,
Type I Diabetes), while the majority (95%) remain healthy. To answer this question genetic and cellular defects in
the immune system were identified and used as the basis for: a. developing experimental models of autoimmune
disease b. comparing regulation of immune responses directly in healthy humans and patients with specific
diseases The results were used as the basis for developing: a. an antibody for treating systemic autoimmune
diseases like RA, now in commercial development (CM) b. a diagnostic kit for identifying cellular defects in
patients with inflammatory bowel disease and other autoimmune conditions, now on the market (BF)

Expected future outcomes:

The insights provided by this research program into the normal functioning of the immune system and
pathogenesis of disease should not only expand our basic knowledge of the immune system but lead to better
diagnostic tests and treatment of autoimmune and allergic disorders.

Name of contact:      Professor Antony Basten
Email of contact:     a.basten@garvan.org.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      219330                                             Start Year:      2003
CIA Name:      Dr Michael S Rolph                                 End Year:        2007
Main RFCD:     Immunology not elsewhere classified                Total funding:   $320,000.00
Admin Inst:    Garvan Institute of Medical Research               Grant Type:      Industry Fellowship


Title of research award: Discovery and validation of therapeutic targets for inflammatory disease using genomic
technologies

Lay Description (from application):

No available Lay Description

Research achievements (from final report):

The aim of the work undertaken in this Industry Fellowship was the discovery of new genes that control
inflammatory diseases such as arthritis and asthma. During the first 2 years of the Fellowship, Dr. Rolph worked
at an Australian biotechnology company, G2 Therapies. During this period the research focussed on the
application of genomic technologies to the discovery of new inflammatory disease genes. A number of new target
genes were discovered. During the third and fourth years of the Fellowship, Dr. Rolph returned to his laboratory at
the Garvan Institute of Medical Research, to continue basic scientific investigations into the new inflammatory
disease genes. The outcome of this work was the demonstration that a number of these genes were intimately
involved in the development of inflammation. These results now provide the basis for subsequent studies
examining new therapies for the treatment of inflammatory diseases such as arthritis and asthma.

Expected future outcomes:

The next step of this project is to test whether drugs that target the new gene products will be of benefit in the
treatment of inflammatory disease.

Name of contact:       Dr. Michael Rolph
Email of contact:      Michael.Rolph@canberra.edu.au
                           NHMRC Research Achievements - SUMMARY
Griffith University

Grant ID:      231421                                           Start Year:      2003
CIA Name:      Dr Nigel A Morrison                              End Year:        2005
Main RFCD:     Rheumatology and Arthritis                       Total funding:   $315,000.00
Admin Inst:    Griffith University                              Grant Type:      Standard Project Grant


Title of research award: Gene related to bone density and fracture.

Lay Description (from application):

Bone density and osteoporosis have a genetic component. Identifying genes that are involved in determining bone
density may permit advances in controlling osteoporosis. We have identified a variant that is related to bone
density high enough to protect individuals four fold against Colle's fracture, the common wrist fracture seen in
women. In addition, some people with bone fracture at the hip, or low bone density, have mutations in this gene.
The gene is a master regulator of the cells that make bone: this gives hope that it may be possible to alter bone
formation through this master regulator.

Research achievements (from final report):

The RUNX2 gene is expressed in both bone and cartilage and is therefore a candidate gene for both osteoporosis
(OP) and osteoarthritis (OA). Not only is RUNX2 important for OP and OA, this gene impacts on periodontal
disease, rheumatoid arthritis, osteomyelitis, loosening of prosthetic devices, and bone loss from malignant cancer.
At least 20% of the population will suffer from one of these conditions in a life time. Runx2 gene variants have
considerable effect on fracture and bone density (BMD). In an average sized school (say 1000 children), 5 will be
carriers of Q-mutants. In a community of 100,000 people, 377 will be carriers of the RUNX2 Q deletions that
confer -0.6SD lower BMD and 133 others will have the 30Q allele that confers -1.1 SD BMD. For every 1SD
decline in BMD, fracture increases two fold. Based on Australia's population, 102,000 people are carriers of Q
mutations and will start life with an increased fracture risk. OP and OA are major causes of morbidity and reduced
productivity due to the demographic trend of increased aged persons as a proportion of the total population.
Osteoporosis Australia estimates that the cost of OP-related fractures and hospitalisation will be $1 billion by
2010. Access Economics claims that the cost of OA to Australia in 2004 was $19.4 billion dollars. This project
has contributed to understanding the genetic influences of RUNX2 on bone and future work will cover influences
on OA.

Expected future outcomes:

Three journal publications are in the process of final editing for submission to top journals such as JBMR. These
papers cover the resubmitted paper on Q-repeat in RUNX2, the influence of 11-Ala polymorphims on fracture risk
and targets of RUNX2 in osteoblasts.

Name of contact:      Nigel Morrison
Email of contact:     N.Morrison@griffith.edu.au
                           NHMRC Research Achievements - SUMMARY
Institute of Medical and Veterinary Science

Grant ID:      242804                                        Start Year:         2003
CIA Name:      Dr Stan Gronthos                              End Year:           2005
Main RFCD:     Cell Development (incl. Cell Division and Apoptosis)              Total funding: $225,000.00
Admin Inst:    Institute of Medical and Veterinary Science   Grant Type:         New Investigator

Title of research award: The molecular mechanisms controlling maintenance of osteoprogenitor precursor cells
and skeletal regeneration.

Lay Description (from application):
Within human bone marrow there exists a rare population of bone marrow stromal stem cells (BMSSCs) able to
develop into the different cell types that form haematopoietic supportive stroma and surrounding skeletal tissue.
There has been alot of interest of late in the potential of BMSSCs as a cellular based therapy to treat and manage
bone fractures or bone loss caused by disease. Increasing evidence suggests that decreased bone mass due to
osteoporosis dos not purely result in an increase of bone resorption by osteoclasts, but may also occur through a
decline in the number of bone forming cells called osteoblasts or their progenitors. Fracture non-union, prosthetic
loosening and the replacement of large defects in bone are common and difficult problems. The use of autologous
bone cells generated from isolated BMSSCs in combination with bio-compatible implant materials would provide
a novel solution for the treatment of these problems, avoiding the use of autografts and allografts of bone with all
their associated difficulties. However, large numbers of ex vivo expanded BMSSCs are currently required to heal
even small bone defects in animal models. This is compounded by the decline in proliferation rates and bone
forming capacity of BMSSCs during prolonged expansion in culture. An improved understanding of the genes that
regulate the proliferation and differentiation of BMSSCs in vitro is therefore an essential prerequisite for the
effective management of bone fracture and bone loss. We propose to genetically manipulate the expression of
genes in BMSSCs, that are known to regulate cellular growth and development inorder to maintain the growth of
stem cell populations in vitro and to extend their capacity to form bone when transplanted in vivo.

Research achievements (from final report):
Bone marrow stromal stem cells (BMSSCs) are being considered as novel therapies for repairing critical size bone
and cartilage defects that normally cannot undergo spontaneous healing. In order to obtain enough numbers of
BMSSCs for cell transplantation, primary BMSSCs need to be expanded extensively in vitro. However, a major
pitfall for ex vivo expansion is that BMSSCs exhibit a limited lifespan in culture and more significantly BMSSCs
gradually lose their capacity to form bone or cartilage in continuous culture. We are the only group capable of
purifying BMSSCs directly from human bone marrow aspirates. Using this technology we are the first group to
characterise the gene expression profile of BMSSC as they exist in the bone marrow. This has enabled us to
identify unique genes that regulate stem cell growth and bone and cartilage cell development. One important
regulatory gene of cellular ageing, telomerase, was found to be highly expressed by BMSSC in vivo, but was
quickly lost following growth in culture. Our studies have shown that telomerase maintains BMSSCs growth in
vitro, by two to three fold. Moreover, our results showed that telomerase-expressing BMSSC mainatined their
stem cell-like qualities in culture and exhibited an increased capacity to generate mineralised bone by up to five
fold following implantation in vivo. These studies will enhance our ability to manipulate and expand BMSSC
populations in culture for subsequent re-implantation in to living tissues in order to treat various orthopaedic
conditions caused by damaged or diseased cartilage and bone.

Expected future outcomes:
Our findings will contribute significantly to our understanding of human skeletal cell development. The use of
BMSSCs in combination with bio-compatible implant materials would provide a novel solution for the treatment
of bone and cartilage loss and repair, avoiding the use of autografts and allografts with all their associated
difficulties.

Name of contact:      Stan Gronthos
Email of contact:     stan.gronthos@imvs.sa.gov.au
                            NHMRC Research Achievements - SUMMARY
Macfarlane Burnet Institute for Medical Research and Public Health

Grant ID:      315425                                         Start Year:     2005
CIA Name:      Prof Phillip M HOGARTH                         End Year:       2007
Main RFCD:     Cellular Immunology                            Total funding: $462,750.00
Admin Inst:    Macfarlane Burnet Institute for Medical Research and Public Health
Grant Type:    Standard Project Grant


Title of research award: The role of Fc receptors in inflammatory disease

Lay Description (from application):

Role of antibodies and their receptors in chronic inflammation: The activation of inflammatory white blood cells
is a major mechanism of tissue destruction in certain autoimmune diseases such as systemic lupus erythematosus
and rheumatoid arthritis. It is well known that destructive chemicals, enzymes and hormones are released by these
cells into affected tissues, for example joints and kidneys. What is lacking is knowledge of the earliest steps in the
immune system that activate the inflammatory white blood cells and drive this inflammation cascade to the point
where chemicals are released and tissued destroyed. This project investigates the role of one of the major receptor
families involved in the activation of inflammation. These are receptors for antibodies called FcR. The binding to
these receptors of unusual antibodies produced in autoimmune disease initiate events that stimulate white blood
cells leading to their activation and the secretion of inflammatory substances. Our work leading up to this project
has been very exciting and has shown that one receptor in particular, FcgammaRIIa is unique to humans, is the
most widespread FcR in the body and is the most potent activator of inflammatory substance release. We will be
studying animal models to precisely define how this human receptor works. Mice have been generated which
contain this uniquely human receptor and these mice develop many features of human autoimmune disease such
as the joint destruction, kidney destruction and lung destruction seen in both rheumatoid arthritis and lupus. The
principal aim of our study is to define the role of this human receptor in the development of inflammatory
conditions with the ultimate goal of using this information to generate new treatments for these diseases.

Research achievements (from final report):

The aim of this project was to define the role of the uniquely human FcgammaRIIa in the develolpment of
antibody dependent tissue destruction with a view to developing new treatments for rheumatoid arthritis and
lupus. We have shown that Fcgamma Receptors play a major role in the development of autoimmune disease by
the characterisation of a unique transgenic mouse showing that FcgammaRIIa is a major activator of antibody-
initiated tissue destruction. The human FcgammaRIIa mice provide a unique, slow onset model for the analysis of
the role of this key receptor in antibody-mediated tissue destruction.

Expected future outcomes:

New targets for therapy and an understanding of the processes that lead to the disruption of regulation of normal
immunity resulting in autoimmune disease. New intellectual property in the form of drug or biological based
therapies protected by patents.

Name of contact:       P. Mark Hogarth
Email of contact:      pmhogarth@burnet.edu.au
                           NHMRC Research Achievements - SUMMARY

Grant ID:      315625                                         Start Year:     2005
CIA Name:      Prof Mark Hogarth                              End Year:       2007
Main RFCD:     Humoral Immunology and Immunochemistry Total funding: $736,500.00
Admin Inst:    Macfarlane Burnet Institute for Medical Research and Public Health
Grant Type:    Standard Project Grant

Title of research award: Structure and function of receptors for IgG (FcgammaR)

Lay Description (from application):
How FcR function in normal and destructive immunity: This research project is studying one of the most
important receptor families of inflammatory white blood cells known in immunology. These receptors called Fc
Receptors (FcR) bind complexes of specialised proteins called antibodies with foreign antigens, i.e. bacteria,
viruses, called immune complexes. As a direct consequence of this binding, a chain of events in inflammatory
white blood cells is set in motion, leading to the destruction of foreign pathogens, however in autoimmune
diseases this same processes leads to the severe inflammation causing destruction of joints in rheumatoid arthritis
and kidneys in glomerulonephritis or allergies, bleeding disorders. Our studies are aimed at understanding the very
first events that initiate this inflammatory cascade, i.e. how immune complexes bind to FcR and having bound
these, how these receptors are organised to initiate the inflammatory cascade. Our studies will use new techniques
such as X-ray crystallography to take 3D photographs of FcR interacting with immune complexes and genetic
engineering studies to validate our 3D photographs. If we understand how immune complexes bind to FcR and
how the receptors are organised on the cell membrane, we will be able to apply this information to the
development of new treatments that either interfere with immune complex binding or receptor organisation.
Although these concepts are well established in other fields e.g. growth hormone receptors, very little is known
about the organisation of receptors involved directly in immunity. These novel studies will provide us with
powerfully useful insights into the first steps in antibody driven tissue destruction.

Research achievements (from final report):

The principal aim of this work was to understand how IgG interact with Fc receptors and the biological
consequences of this interaction (eg. activating and/or regulatory responses and relevance to pathology). It was a
multidisciplinary project using Xray crystallography, protein reconstitution studies, mutagenesis and cell-based
functional assays to analyse IgG and FcR family member interactions. The work we accomplished includes: 1) the
first crystal structure of a human IgG in complex with the activating receptor FcgammaRIIa; 2) extended our
analysis to other related FcgammaR's; 3) been able to show that anti-FcgammaRIIa antibodies may be effective
therapeutics in arthritis.

Expected future outcomes:

This work will lead to the design of new anti-inflammatory protein and drugs that antagonise Fc receptor function.
Also to understandingt the mechanisms by which antibodies and Fc receptors activate/inhibit leukocytes in normal
and autoimmunity. In addition, understanding of Ig FcR interaction will lead to improved therapeutic antibodies
for the treatment of diseases such as cancer.

Name of contact:      Professor Mark Hogarth
Email of contact:     pmhogarth@burnet.edu.au
                            NHMRC Research Achievements - SUMMARY
Monash University

Grant ID:      143549                                            Start Year:      2001
CIA Name:      A/Pr Merrill J Rowley                             End Year:        2003
Main RFCD:     Rheumatology and Arthritis                        Total funding:   $225,000.00
Admin Inst:    Monash University                                 Grant Type:      Standard Project Grant

Title of research award: Functional effects of antibodies to collagen on cartilage synthesis and degradation
Lay Description (from application):
It has been shown that antibodies to collagen type II in cartilage occur in ~70% of patients with early rheumatoid
arthritis, suggesting that autoimmunity to cartilage collagen may play a part in the devleopment of this destructive
arthritis. An animal model widely used as a model of human RA is the disease collagen induced arthritis (CIA). It
is induced by immunisation of mice with collagen II; antibodies to collagen II are critical for the development of
CIA. However not all such antibodies are disease-associated. There may be particular regions on the collagen
molecule where antibody-binding causes damage. This project is based on the hypothesis that antibodies to
collagen type II, which transfer arthritis in mice, are those that react specifically with regions of the collagen
fibrils that are crucial for cartilage stability and function. We plan to test this hypothesis in an in vitro system
using cultured cartilage. We predict, based on our preliminary data, that antibodies to collagen II from mice with
CIA will interfere with the normal assembly and structure of cartilage. We will test this by adding antibodies
under precisely defined conditions to cultured cartilage, and analysing the matrix that is synthesised. The study
would then be extended to RA with a comparison of the regions of collagen II that react with antibodies of mouse
and human origin. Showing that antibodies to collagen II are directly destructive, allowing for an understanding of
their site and mode of action, would greatly advance our understanding of the cause of RA and would lead to more
effective forms of treatment.

Research achievements (from final report):
Antibodies to type collagen II (CII, cartilage collagen) occur in serum and synovial fluid from patients with
rheumatoid arthritis (RA), and can be detected in most patients early in the disease. The aim of this project was to
establish whether antibodies to CII that are present in the serum of patients with rheumatoid arthritis (RA) could
affect the development and stability of the collagen fibrils that are an essential component of normal articular
cartilage. We used monoclonal antibodies to CII from mice with collagen-induced arthritis (CIA), that results
from immunization with collagen II; the mouse antibodies react with precisely the same regions of the CII
molecule as human antibodies in RA. Antibodies to CII are critical for the development of CIA, but not all such
antibodies are disease-associated and there may be particular regions on the collagen molecule where antibody-
binding would cause damage. The cartilage in the joint is a complex network of fibrils of collagen that entraps
highly charged proteoglycans. The interactions between these components gives cartilage its structural stability,
and particular antibodies to CII may interfere with such interactions. We examined the effects of antibodies to CII
on the development of cartilage in cultures of chondrocytes, the cells that produce cartilage, and also their effects
on pre-formed cartilage, using cartilage explants. The study showed that mouse antibodies to CII that could
transfer arthritis in vivo interfered with the molecular interactions essential to cartilage structure and integrity,
causing changes in the structure of the collagen fibrils and adversely affecting the chondrocytes themselves. The
changes observed occurred both in newly formed cartilage, and also in pre-formed cartilage, and were associated
with antibodies that could transfer arthritis in vivo, but not with non-arthritogenic antibodies. They represent an
entirely new and unsuspected mechanism of joint damage in arthritis.

Expected future outcomes:
The demonstration that autoantibodies to type II collagen can affect the structural stability of cartilage, and hence
could lead to further joint destruction, provides important new insights into mechanisms of damage in rheumatoid
arthritis, in which such antibodies are known to occur. The knowledge could be important for the development of
new forms of treatment of RA.

Name of contact:       Merrill Rowley
Email of contact:      Merrill.Rowley@med.monash.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      143707                                           Start Year:      2001
CIA Name:      A/Pr Michelle T Leech                            End Year:        2003
Main RFCD:     Rheumatology and Arthritis                       Total funding:   $110,000.00
Admin Inst:    Monash University                                Grant Type:      New Investigator


Title of research award: MIF and p53 in inflammatory arthritis

Lay Description (from application):

Rheumatoid arthritis (RA) is an inflammatory disease affecting approximately 1% of the population. It is
characterised by severe inflammation and destruction of joints resulting in significant health problems. The lining
tissue of joints is known to be infiltrated by inflammatory cells. In addition to this infiltration of inflammatory
cells, there is overgrowth of the normal lining cells of joints. These overgrowing cells contribute significantly to
joint damage by invading cartilage and bone and allowing inflammatory cells to reach these areas. The abnormal
growth of these cells has been related to the malfunction of certain genes that usually restrain abnormal growth.
These genes called tumour suppressor genes are known to be damaged in joint lining cells derived from RA. The
best known of these abnormal tumour suppressor genes is called p 53. The product of the p53 gene, the p 53
protein, is particularly important in slowing down the growth of cells. The applicant has recently shown that an
inflammatory product called MIF is released in large quantities by joint lining cells in RA. Previous studies by the
applicant have shown that blocking MIF using an antibody almost completely prevents arthritis development in a
rat model. These studies indicate that MIF is likely to be an important contributor to disease in RA. Recent
preliminary studies in the applicant s laboratory have shown that MIF can decrease p53 levels in joint lining cells
from RA patients and also that MIF can increase the growth rate of these cells. These preliminary data indicate
that MIF may contribute significantly to disease in RA by overriding control of normal cell growth by p53.
Confirmation and full exploration of the regulation of p53 expression and function by MIF may highlight a novel
way to treat the excessive growth and invasion by joint lining cells which characterises RA.

Research achievements (from final report):

The aim of this study was to examine the role of an inflammatory substance (cytokine ) in this case called
macrophage migration Inhibitory factor (MIF) to influence a protein involved in cell growth control called protein
53 (p 53). The capacity of inflammatory substances produced in the arthritis process to influence cell growth is
particularly relevant in rheumatoid arthritis where the overgrowth of inflamed joint lining cells and tissue is
important in causing joint damage and deformity. In these studies it was shown that animals deficient in this
cytokine (MIF knock-out mice) have reduced severity of arthritis and this is associated with a protective effect of
increases in p53 which could function to slow down overgrowth of inflammatory tissue. It was also shown that
this cytokine could directly decrease levels of this growth protein p53 in cells derived from human rheumatoid
arthritis patients.

Expected future outcomes:

Therapeutic strategies which target MIF are currently in development and are intended for the treatment of chronic
inflammatory diseases, including RA. Understanding the role of this cytokine in the regulation of a key cell cycle
protein like p53 is an important prelude to the application of such therapies.

Name of contact:      Dr Michelle Leech
Email of contact:     michelle.leech@med.monash.edu.au
                             NHMRC Research Achievements - SUMMARY

Grant ID:      194439                                              Start Year:      2002
CIA Name:      Prof Flavia Cicuttini                               End Year:        2003
Main RFCD:     Epidemiology                                        Total funding:   $75,000.00
Admin Inst:    Monash University                                   Grant Type:      Standard Project Grant


Title of research award: The Predictors Of Knee Cartilage Loss - A 5-Year Natural History Study Based On An
Existing Cohort

Lay Description (from application):

Osteoarthritis (OA) is the single biggest cause of disability in Western society. Despite this, relatively little is
known about the factors that effect disease progression. This will be the first extended follow up study of cartilage
volume in people with early OA. This study will build on our existing work where we have developed a cohort
study of adults with early knee OA. These people were initially recruited in 1997/8. An extensive data base of
potential risk factors for OA has been collected and both X-rays of the knee and MRI have been performed at
baseline and 2 years. Extending the follow up from 2 to 5 years will allow not only more precise estimation of
rates of cartilage loss and assessment of risk factors, but also enable assessment of the assumption of linearity of
cartilage volume loss. It will also be possible to partition the observed variability in rates of loss into true between-
subject variability and within subject residual variability. This partitioning will provide valuable information for
the design of future studies in OA, similar to the establishment of statistical design principles for patterns of loss
in bone mineral density.

Research achievements (from final report):

We have been able to show that the rate of knee cartilage loss as measured by a novel MRI based method for
measuring knee cartilage, predicts who proceeds to a knee replacement among those with knee osteoarthritis

Expected future outcomes:

We are now exploring both lifestyle factors (such as diet and physical activity) to determine which factors will
prevent the loss of knee cartilage and thus joint replacement.

Name of contact:       Flavia Cicuttini
Email of contact:      flavia.cicuttini@med.monash.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      237048                                            Start Year:      2003
CIA Name:      A/Pr Eric F Morand                                End Year:        2004
Main RFCD:     Medical Biotechnology                             Total funding:   $85,000.00
Admin Inst:    Monash University                                 Grant Type:      Development Grant


Title of research award: The Development Of Novel Anti-Inflammatory Compounds

Lay Description (from application):

The cytokine macrophage-migration inhibitory factor (MIF) has a broad range of pro-inflammatory effects in the
innate and adaptive immune system. CIA’s lab has demonstrated the potential importance of MIF in the pathology
of chronic inflammation via studies in models of rheumatoid arthritis (RA). Similarly to other chronic
inflammatory diseases, MIF is overexpressed in human RA, and induces activation of key pathological processes
in RA cells. Moreover, antagonism of MIF with mAb profoundly inhibits models of RA and other inflammatory
diseases, confirming MIF as a therapeutic target in human inflammatory disease. The X-ray crystal structure of
MIF has been published and the putative active site fully characterised. We have deduced structural features of
MIF that reveal aspects of the structural complementarity of host-guest affinity. This information has been used in
the synthesis of new compounds to antagonise MIF. We have designed, synthesised and tested several classes of
compounds, which have shown activity from milli to nano-molar levels in novel in-house in vitro bioassays.

Research achievements (from final report):

Inflammation is the causative process of human diseases as diverse as rheumatoid arthritis and atheroscloerosis.
Current treatments for inflammatory diseases are limited by side ffects, ineffectiveness, cost, or all of these. There
is a need for better, more economical treatments to inflamamtory diseases. Macropahge migration inhibitory factor
(MIF) is a protein critical to the development of inflammation. Blocking MIF has been shwon to be helpful in
models of inflammatory diseases, but no current drugs act by blocking MIF. The research funded by this grant
supported the development of antagonists or 'blockers' of MIF which have the potential to be developed into new
treatments which deal with the problems of current drugs. The major outcome of this work was the confirmation
that MIF antagonist compounds can indeed be made and do indeed have the expected effectiveness in models of
inflammatory diseases such as arthritis. This has lead since to a major commercial udnertaking via a 'startup'
company, to develop MIF antagonists as human therapies.

Expected future outcomes:

Further development of the prototype 'lead' compounds under investigation could lead to the commencement of
clinical trials in the next 2 years.

Name of contact:       Eric Morand
Email of contact:      eric.morand@med.monash.edu.au
                           NHMRC Research Achievements - SUMMARY

Grant ID:      143789                                           Start Year:      2001
CIA Name:      Prof Stephen R Holdsworth                        End Year:        2005
Main RFCD:     Clinical Sciences not elsewhere classified       Total funding:   $4,100,000.00
Admin Inst:    Monash University                                Grant Type:      Program Grant


Title of research award: The Regulation of Organ Specific Inflammatory Disease

Lay Description (from application):

No available Lay Description

Research achievements (from final report):

Demonstration of the relative contributions of the coagulant and immune stimulating contributions of tissue factor
to glomerular inflammation o Confirmation that tissue factor on immune cells signals immune activation o
Definition of the involvement of tissue factor (as well thrombin) via signally through PAR receptors induces
arthritis in an antigen induced model in mice o Demonstration of the important role of tissue factor in
endotoxaemia T-cells in Crescentic Glomerulonephritis Definition of: o The relative contributions and
mechanisms of action of CD80 and CD86 in experimental crescentic GN o The multiple independent roles of
CD40 in the generation and mediation of nephritogenic immunity in crescentic GN, including the role of CD40 on
intrinsic glomerular cells o The role of cytokines determining critical pathological outcomes in GN including IL-
18, IL-13 and IL-12 o Developed a new model of murine experimental anti-neutrophil antibody mediated
crescentic GN that demonstrated a key role for T-cell effectors o Firmly established the cytokine network between
immune cells and intrinsic cells inducing crescentic GN o Established a system for defining migration of
leukocytes into glomeruli. This system was establised using intra vital microscopy o That ANCA can directly
induce neutrophil migration into glomeruli o Defined the protective roles of co-stimulatory molecule OX40
experimental anti-GBM GN and interferon gamma in autoimmune anti-GBM GN Cytokine and Glucocorticoid
Regulation of Inflammatory Arthritis o Discovery and development of small molecule antagonists of the cytokine
MIF, which form a potential new class of therapy for immune and inflammatory diseases o Definition of the role
of Annexin-1 in arthritis o Dissection of MIF induced cell signalling in regulating inflammation o The expression
and function of glucocorticoed induced MAP kinases in inhibiting MKP-1 in human arthritis was demonstrated

Expected future outcomes:

These studies have defined critical molecular steps in the induction of injurious inflammation in the kidney and
joints. These advances will allow new therapeutic approaches to add to the treatment of arthritis and
glomerulonephritis. Growing biotech commercial partnerships are advancing new therapies based on this work.

Name of contact:      Professor Stephen Holdsworth
Email of contact:     Stephen.Holdsworth@med.monash.edu.au
                           NHMRC Research Achievements - SUMMARY

Grant ID:     194318                                           Start Year:      2002
CIA Name:     A/Pr Peter G TIPPING                             End Year:        2006
Main RFCD:    Nephrology and Urology                           Total funding:   $115,000.00
Admin Inst:   Monash University                                Grant Type:      NHMRC Research Fellowship


Title of research award: Research fellowship

Lay Description (from application):

No available Lay Description

Research achievements (from final report):

This project investigated mechanisms of inflammatory injury in nephritis, arthritis and sepsis. It explored the
interactions between coagulation molecules (and their receptors) and inflammatory pathways in murine models of
inflammation, and demonstrated that activation of these receptors agumented systemic , renal and joint injury.
Therapies targetted at these coagulation molecules and their receptors may prove beneficial in these inflammatory
diseases.

Expected future outcomes:

This project aims inprove knowledge of pathogenic mechanisms in inflammatory diseases affecting the kidney,
and joints and in systemic sepsis and define new targets for therapetic internention.

Name of contact:      A/Prof Peter Tipping
Email of contact:     peter.tipping@med.monash.edu.au
                           NHMRC Research Achievements - SUMMARY

Grant ID:      284231                                           Start Year:      2004
CIA Name:      A/Pr Michelle T Leech                            End Year:        2006
Main RFCD:     Immunology not elsewhere classified              Total funding:   $235,500.00
Admin Inst:    Monash University                                Grant Type:      Standard Project Grant

Title of research award: Regulation of leukocyte trafficking by macrophage migration inhibitory factor (MIF)

Lay Description (from application):
The entry of white blood cells in to tissues is a primary event which drives tissue and organ damage in a number
of inflammatory and immune mediated conditions. Diseases as diverse as rheumatoid arthritis, lupus or shock due
to bacterial infection (septic shock) have many different triggers and manifestations. However almost all
autoimmune and inflammatory diseases have one common feature: white blood cells must leave the blood and
enter tissue in order to cause tissue inflammation and ultimately tissue damage and loss of function. The
mechanism whereby white blood cells leave the blood stream and cross blood vessel walls to get into tissues is a
multi-step process often referred to as white blood cell trafficking. Most of the current treatments for immune and
inflammatory conditions have the primary aim of keeping white blood cells out of tissue in order to prevent
damage. Some of these treatments, like steroids (cortisone), are very effective but cannot be used for prolonged
periods because of the risk of problems like bone thinning (osteoporosis), high blood pressure or diabetes. Other
treatments and immunosuppressive agents can also be effective but are themselves associated with toxicity and
risk of organ damage. Although substantial progress has been made in the management of immune and
inflammatory conditions in the last 50 years, the current treatment options are far from ideal. Macrophage
migration inhibitory factor (MIF) is an inflammatory substance released by cells which comprise the blood vessel
wall as well as by white blood cells themselves. It is known to contribute to the build up of white blood cells in
inflamed tissue. The effect of MIF on white blood cell trafficking has never been examined. Understanding how
MIF promotes white cell entry in to tissues could be crucial in our understanding of this important process and
blocking MIF may prove to be a useful and effective way to prevent it.

Research achievements (from final report):

Macrophage migration inhibitory factor (MIF) is important in the development of inflammatory responses such as
arthritis and experimental models of multiple sclerosis. Although some mechanisms to explain this have been
determined, little is known about the ability of MIF to regulate one of the damaging components of inflammation -
white blood cell (leukocyte) recruitment. Therefore the aim of this project was to test the hypothesis that MIF
enhances inflammation via the promotion of leukocyte recruitment. To achieve this aim we compared
inflammatory responses in blood vessels of normal mice with those in mice genetically-deficient in MIF (MIF-/-
mice). In response to various inflammatory stimuli, we observed that in mice lacking MIF, white blood cells stuck
to blood vessel walls and entered inflamed tissues much less efficiently, indicating that MIF promotes this process
of leukocyte accumulation. Further analysis indicated that this effect was not due to an interaction of MIF with the
circulating anti-inflammatory hormones known as glucocorticoids (GC). These were the first experiments to show
that MIF affects this key element of the inflammatory response. We also found that application of MIF directly to
tissues caused leukocyte migration into that tissue. Importantly MIF attracted one type of leukocyte predominantly
- the macrophage. This type of white blood cell is an important damaging cell in diseases such as atherosclerosis
and arthritis. Our findings suggest that MIF may contribute to these diseases by promoting accumulation of this
damaging cell type in affected tissues, and that inhibiting MIF may be protective in these diseases.

Expected future outcomes:
This project has identified a new function for the inflammatory protein MIF, in that it promotes the entry of white
blood cells into inflamed tissues. This work suggests that drugs designed to inhibit the function of MIF may
reduce inflammation in various diseases, in part by preventing white cell accumulation

Name of contact:      Dr. Michael Hickey
Email of contact:     michael.hickey@med.monash.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      284354                                            Start Year:      2004
CIA Name:      Prof Rachelle Buchbinder                          End Year:        2007
Main RFCD:     Endocrinology                                     Total funding:   $578,000.00
Admin Inst:    Monash University                                 Grant Type:      Standard Project Grant


Title of research award: Efficacy and safety of vertebroplasty for treatment of painfrul osteoporotic spinal
features: a randomised trial

Lay Description (from application):

Painful spinal or vertebral fractures are a substantial and growing public health problem and are a burden on the
health care system. In Australia, 20-25% of women and 15-20% of men over the age of 50 will develop one or
more fractures of their spine in their lifetime. Up to a half of these fractures will result in severe pain and
disability. While the fractures generally heal within weeks or a few months, some are so painful that they require
narcotic pain control, hospitalisation, and/or long-term nursing home care. Other problems include chronic pain,
spinal deformities, loss of height and mobility and restricted breathing. Vertebroplasty is a new procedure
consisting of injection of a type of 'bone cement' into the vertebrae to mend the break. It is an exciting treatment
because for some people, this results in an immediate and sustained improvement in pain. Although rare,
complications such as rib fracture, cement leakage and fractures in other vertebrae do occur. One particular
concern is that the mechanical changes to the spine caused by the bone cement may cause long-term
complications such as an increased risk of future fractures of treated or adjacent vertebrae. So far, there is very
little evidence of the efficacy and safety of this new technology. Importantly, it has not been compared with usual
medical care for fractures. In medical research it can be difficult to properly evaluate an exciting and 'apparently'
effective treatment that doctors and patients demand. The main aim of this project is to determine whether
vertebroplasty is an effective and safe treatment compared to usual medical care. We have a unique opportunity to
evaluate vertebroplasty through a strong collaborative effort between the 3 centres currently offering this
procedure in Melbourne. If vertebroplasty can be demonstrated to be an effective, safe and cost-effective
treatment for painful osteoporotic spinal fractures this will be a valuable addition to current treatment options.

Research achievements (from final report):

Painful vertebral fractures complicating osteoporosis are a substantial and growing public health problem leading
to severe morbidity and an increased burden on the health care system. Vertebroplasty is becoming an
increasingly accepted treatment for vertebral fractures despite the lack of scientific evidence of its benefit. The
outcome of our proposed research will be to establish whether vertebroplasty is efficacious, safe, and cost-
effective compared to placebo for painful osteoporotic spinal fractures. If positive, we will have scientific
evidence to support the currently uncorroborated widespread endorsement of this intervention. If, on the other
hand, our results indicate that its efficacy is no greater than placebo (and it may do more harm), then the resources
spent on performing these procedures might be put to better use. We have published an editorial outlining our
concerns about use of vertebroplasty without high quality evidence of its benefit.

Expected future outcomes:

We will determine the short term efficacy and safety of vertebroplasty for alleviating pain and improving function
for acute painful osteoporotic vertebral fractures and examine if there is excess risk of further vertebral fractures
within two years.

Name of contact:       Professor Rachelle Buchbinder
Email of contact:      rachelle.buchbinder@med.monash.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      334150                                             Start Year:      2005
CIA Name:      Prof Flavia Cicuttini                              End Year:        2007
Main RFCD:     Rheumatology and Arthritis                         Total funding:   $0.00
Admin Inst:    Monash University                                  Grant Type:      Standard Project Grant


Title of research award: Effect of lifestyle factors on knee cartilage and rate of cartilage loss in a normal
population

Lay Description (from application):

Osteoarthritis (OA) has been described by the WHO as a potential epidemic and a major health and care services
cost driver in an aging society. OA has the largest impact on burden of disease borne in later life. This has been
acknowledged by its listing as the 7th health priority in Australia. To date, most research has focused on treating
the resulting pain and disability. However, in order to reduce the burden of OA, identifying modifiable risk factors
in the normal population is important. This proposal aims to identify life-style factors, such as diet, physical
activity and obesity that effect knee cartilage health in healthy subjects, thereby identifying potential targets for
future prevention of OA. This will provide us with the opportunity to promote a better quality of life as people age
and reduce the economic burden on the community.

Research achievements (from final report):

In this cohort study, we examined the relationship between lifestyle factors including diet, obesity, and physical
activity and knee cartilage and bone health in healthy people without history of knee osteoarthritis or injury. We
have found that intake of vitamin C and fruit, muscle mass, and physical activity are beneficial to joint health, and
that intake of fatty acids and fat mass are detrimental to joint health. Osteoarthritis is a major cause of pain and
disability in elder population. It has been described by the WHO as a potential epidemic and major health and care
service cost driver in an aging society and listed as the 7th national health priority in Australia. There is no cure
for knee osteoarthritis and joint replacement is approached for the treatment of end-stage symptomic
osteoarthritis. Osteoarthritis has the largest impact on burden of disease borne in later life. To date, most research
has focused on patients with established osteoarthritis. Therefore, in order to reduce the burden of osteoarthritis, it
is more important to identify modifiable lifestyle factors which may contribute to the risk of osteoarthritis in the
normal population. This study has the potential to identify potential targets for future prevention of knee
osteoarthritis, and provide us with the opportunity to promote a better quality if life as people age and reduce the
economic burden on the community.

Expected future outcomes:

We will continue the research to examine the effect of bone marrow lesions in the development of knee
osteoarthritis. We will aslo examine the relationship between body composition and physical activity and the
change in knee structures.

Name of contact:       Flavia Cicuttini
Email of contact:      flavia.cicuttini@med.monash.edu.au
                           NHMRC Research Achievements - SUMMARY

Grant ID:      284402                                           Start Year:      2004
CIA Name:      Dr Donna M Urquhart                              End Year:        2008
Main RFCD:     Orthopaedics                                     Total funding:   $64,750.00
Admin Inst:    Monash University                                Grant Type:      Australian Clinical Research
                                                                Fellowship


Title of research award: The characterisation of orthopaedic trauma and the evaluation of outcome.

Lay Description (from application):

No available Lay Description

Research achievements (from final report):

Musculoskeletal conditions are major contributors to pain and disability in Australia, with more than 6.1 million
people affected. Moreover, with aging of the population and the obesity epidemic, these figures are expected to
rise. As a result, musculoskeletal conditions have been declared a National Health Priority. This research program
was aimed at investigating risk factors, outcomes and treatment strategies for musculoskeletal conditions,
including the two most common muscloskeletal conditions, low back pain and osteoarthritis. Some of the key
findings from our research program included; identifying that both high levels of back pain and disability are
associated with obesity in community-based women and that while knee malalignment is associated with
progression of knee osteoarthritis, there is insufficient evidence to support a relationship with the development of
this condition. With respect to outcomes, we found a large percentage of patients after musculoskeletal injury have
ongoing pain and disability and a reduced capacity to return to work 6 months after their trauma and that partial
and revision hip replacements are resource intensive for the public and private health-care systems, respectively.
Moreover, we found that there is no clear evidence to support the use of two common treatment strategies, anti-
depressants and radiofrequency deinnervation, for the management of low back pain. This work has the potential
to guide health and medical researchers in future epidemiological research into low back pain and osteoarthritis,
inform health services in the outcomes and resource utilisation associated with these conditions, and assist
clinicians in the selection of treatment strategies in the management of musculoskeletal pain and disability.
Ultimately, the findings of this research program will assist in the future development of innovative strategies to
prevent and manage chronic pain and disability associated with musculoskeletal conditions.

Expected future outcomes:

The findings of this research program will assist in the future development of innovative strategies to prevent and
manage chronic pain and disability associated with musculoskeletal conditions.

Name of contact:      Donna Urquhart
Email of contact:     Donna.Urquhart@med.monash.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      334060                                            Start Year:      2005
CIA Name:      A/Pr Sally E Green                                End Year:        2008
Main RFCD:     Primary Health Care                               Total funding:   $426,000.00
Admin Inst:    Monash University                                 Grant Type:      Standard Project Grant


Title of research award: Implementing Clinical Practice Guidelines in General Practice: A Cluster Randomised
Controlled Trial

Lay Description (from application):

Evidence based clinical practice guidelines have the potential to improve clinical practice through providing
health care workers with the most reliable information on which to base their treatment decisions. Many
governments and organisations are investing significantly in the development of guidelines for common and
important clinical disorders. To date, however, we do not fully understand how to increase the uptake of
guidelines and facilitate health care workers to change their practice in line with the guideline's recommendations.
This project aims to work with general practitioners to develop a method or strategy to increase the uptake of
guidelines for the treatment of acute low back pain, particularly to reduce the number of patients who are
unnecessarily x-rayed, and to increase advice to stay active. The effectiveness of the developed strategy will be
tested by randomly assigning general practice clinics to either receive the intervention or to have access to the
guidelines without any extra interventions (such as training and reminders) to help doctors change their practice.
Both the doctor's practice, and patient outcomes of pain and disability will be measured to determine not only if
the doctors followed the guidelines, but whether this resulted in an improvement in patient outcome. The findings
of this study will help us understand the best ways to improve adhesion to guidelines and so has the potential to be
applied to other conditions presenting to general practice where there are recommendations not currently being
implemented into practice.

Research achievements (from final report):

This project evaluated an intervention designed to assist general practitioners better manage people with acute
low-back pain. The study has shown that the GPs who received the intervention intended to order less x-rays and
intended to give advice to stay active more often to their patients with acute low-back pain. This research has led
to further articulation of the complexities of this kind of research that aims to improve clinical practice, and has
thus furthered understanding in the field of implementation science. This project has also extended the
methodology of the development of theory-based complex interventions, and the assessment of complex
intervention fidelity. Also, this project will inform healthcare policy by providing some answers about the
implementation of guidelines in general practice. Finally, the project has strengthened partnerships between the
Australian-based project team and international colleagues.

Expected future outcomes:

GPs ordering less x-rays for patients with acute low-back pain can lead to reduced healthcare costs and decreased
number of people exposed to harmful radiation. The increased use of GPs giving patients with acute low-back
pain advice to stay active should result in improved healthcare outcomes. Methods development have contributed
to our understanding of translation of research into practice.

Name of contact:       Professor Sally Green
Email of contact:      sally.green@med.monash.edu.au
                            NHMRC Research Achievements - SUMMARY

Murdoch Childrens Research Institute

Grant ID:      284524                                           Start Year:        2004
CIA Name:      Prof John F Bateman                              End Year:          2006
Main RFCD:     Cellular Interactions (incl. Adhesion, Matrix, Cell Wall)           Total funding: $486,168.00
Admin Inst:    Murdoch Childrens Research Institute             Grant Type:        Standard Project Grant


Title of research award: The role of the extracellular matrix protein, WARP, in cartilage development, function
and pathology

Lay Description (from application):

The environment outside all cells is absolutely essential for normal growth and development. In order to
undertand many disease and developmental processes it is critical that we acquire a detailed understanding of the
various extracellular matrix components and how they interact to form a functional extracellular matrix. We
recently discovered a new extracellular matrix protein which we have named WARP for von Willebrand factor A-
domain-related protein. Our experiments demonstrate that WARP is an important constituent of the three-
dimensional structure of the extracellular matrix of the articular surface of cartilage. We can show that WARP
forms large-scale structures in tissue culture experiments and in extracts from mouse cartilage, and we have some
new data which suggests that WARP interacts specifically with collagen II, a large and quantitatively major
component of cartilage. We will explore the function of WARP in cartilage and include in vitro experiments that
will reveal information about its distribution, tissue forms, and interactions with other extracellular matrix
components (PART 1). To define the in vivo role of WARP we will generate a WARP gene knockout mouse
(PART 2). These experiments will provide valuable information about the structure of the cartilage in the joint on
the surface of bone and in particular the function of WARP in this structure. Since WARP is at the articular
cartilage surface we asked whether WARP is lost in cartilage degeneration. In cartilage tissue grown in vitro under
conditions that promote cartilage degradation, WARP is fragmented and released from the cartilage surface. We
will explore this further in in vitro and in vivo models of cartilage breakdown (PART 3). Thus, in addition to
promoting a new understanding of cartilage structure WARP has the exciting potential to become a specific
biomarker for arthritis a major joint degenerative disease with high medical and financial cost to the community.

Research achievements (from final report):

We discovered and chararerised a new protein in cartilage, showing how it interacted with other proteins to
establish the intergrity of the cartilage tissue. We studied when and when this protein was prodcued during
development of the mouse skeleton. This new protein, called WARP, was found exclusively at the surface of the
articular cartilage, making it a good candidate for use as a clinical marker of cartilage destruction in arthritis.
Studies were initiated to determine its utility as a biomarker of arthritis.

Expected future outcomes:

A clinical testing procedure will be developed to evaluate its use as a biomarker of arthritis in patients with
arthritis.

Name of contact:       John Bateman
Email of contact:      john.bateman@mcri.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      384414                                            Start Year:      2006
CIA Name:      Prof John F Bateman                               End Year:        2008
Main RFCD:     Orthopaedics                                      Total funding:   $448,500.00
Admin Inst:    Murdoch Childrens Research Institute              Grant Type:      Standard Project Grant


Title of research award: Molecular mechanisms of cartilage degeneration in osteoarthritis

Lay Description (from application):

Arthritis affects 15% of the entire Australian population and 50% in people over 60. The most common form of
joint disease by far is osteoarthritis (OA). One of the central features of OA is the breakdown of the cartilage that
covers the ends of bones in joints, and this is a major determinant of the long term outcome and need for joint
replacement surgery. There are no current therapies that halt or reverse cartilage breakdown in OA. This is largely
due to our incomplete understanding of the molecular changes and pathways involved in both the onset and
progression of cartilage breakdown. Powerful new genomic approaches allow simultaneous screening of changes
in a broad profile of genes, particulalrly in humans and mice following complete sequencing of their genomes. By
applying this new technology in the earliest stages of cartilage degeneration in OA, the role of novel genes and the
pathways involved in the onset of this disease process can be discovered. However, to investigate changes at the
initiation of disease, tissue from animal rather than human joints must be used due to the difficulty in obtaining
pre-symptomatic human cartilage. In order to maximise the number of genes screened, cartilage from a novel
surgically induced model of OA in mice will be used in this study. We have developed micro dissection and linear
mRNA amplification methods to overcome inherent problems with tissue availability from this small animal
species. Successful completion of these studies will for the first time allow identification of the complex changes
that occur in early OA. An important and likely outcome of this research will be identification of novel matrix
proteins and regulatory molecules that will provide critical information for the development of new diagnostic and
therapeutic approaches to OA.

Research achievements (from final report):

This is the first study to comprehensively determine the gene expression patterns of cartilage during the initiation
and progression of osteoarthrtitis. It has identified new genes that may play a role in either the onset or
development of joint disease. Because these studies have identified possible new molecular pathways that may be
involved in OA, the information obtained in these studies has potential for the development of novel biomarkers
ans therapeutic approaches

Expected future outcomes:

The novel OA candidate genes identified in this study will be examined in detail ongoing studies. The outcome of
these studies is likely to be a more complete elucidation of OA disease mechanisms.

Name of contact:      John Bateman
Email of contact:     john.bateman@mcri.edu.au
                            NHMRC Research Achievements - SUMMARY
Queensland University of Technology

Grant ID:      138711                             Start Year:    2001
CIA Name: Dr James E Smeathers                    End Year:      2003
Main RFCD: Biomechanical Engineering              Total funding: $185,000.00
Admin Inst: Queensland University of Technology   Grant Type: Standard Project Grant
Title of research award: QUANTITATIVE ASSESSMENT OF LOOSENING IN HIP ARTHROPLASTIES
USING MECHANICAL VIBRATION DIAGNOSTICS

Lay Description (from application):

Recent advances and improvements made to the mechanical design of artificial joints have led to greater strength,
fatigue life and wear resistance. However, this extension to the working life of joint replacements has led to
patients becoming increasingly vulnerable to the problem of joint loosening. There are over 500 000 hip joint
replacements performed every year, on a worldwide basis. Of these 7 to 13% will require revision surgery because
of loosening at some stage of their working life. This is becoming a major concern to health services around the
world since revision surgery is associated with a higher risk to the patient and costs are far greater than for the
primary operation. Current diagnostic techniques using radiographic imaging are both invasive and lack diagnostic
accuracy. The ability to detect joint loosening and to discriminate between the various causes of joint loosening
following arthroplasty is of great importance to the success of subsequent care plans. This study will be the first in
the world to assess the validity of a new diagnostic test that uses low energy mechanical vibration to quantify the
degree of loosening in both components of the implanted hip joint. Once the technique has been proven it could
readily be extended to evaluate the degree of fixation of other implanted prostheses used to replace the knee, ankle
or joints of the upper limbs.

Research achievements (from final report):

This research program has significantly advanced the way that loosening of artificial hip joints is detected by
using low energy mechanical vibration to provide a safe additional means of evaluating the integrity of an implant
in the human body. The significance of this relates to the 500 000 hip joint replacements that are performed
worldwide annually. Unfortunately, up to 8% of these implants will suffer from aseptic loosening which, is
thought to be caused by tissue reaction to wear debris and resorption of the supporting bone. There is growing
concern over the increasing numbers of artificial joints that are failing by loosening due impart to the large
numbers in service and the trend to earlier implantation in younger more active patients. It is still difficult to
diagnose aseptic joint loosening with current clinical imaging techniques where loosening is confirmed by a
combination of invasive radiographic techniques, radio-opaque dyes injected into the joint space, pain provocation
tests and ultimately, physical assessment at the time of surgery. Hence this research evaluates a complimentary
diagnostic technique that is based on mechanical vibration to detect structural changes within the human body.
The principles of vibration based monitoring previously developed by engineering and aerospace industries to
detect failure in machinery is now being applied to the human body and the problem of loosening in artificial
joints. The potential of this novel application to the clinical problem of artificial joint loosening has been
examined by this research project under extensive laboratory tests and early clinical trials. In principle, this
additional diagnostic test will help improve the health of Australians through improved accuracy of diagnosis and
efficiency of surgical care by assisting the surgeon to make better informed decisions on whether or not to
reoperate on the joint and how to optimise the timing of revision procedures.

Expected future outcomes:
In the longer term knowledge gained from this research coupled with improvements in technology will enable a
clinical diagnostic device, for detecting loosening of artificial joints, to be manufactured in Australia and marketed
throughout the world. The diagnostic principles of this system will also have relevance to a wide range of other
structural problems and discipline areas.

Name of contact:       James Smeathers
Email of contact:      j.smeathers@qut.edu.au
                            NHMRC Research Achievements - SUMMARY
Royal Melbourne Institute of Technology

Grant ID:      140512                                           Start Year:       2001
CIA Name:      A/Pr Janine A Danks                              End Year:         2006
Main RFCD:     Systems Physiology                               Total funding:    $450,612.83
Admin Inst:    Royal Melbourne Institute of Technology          Grant Type:       NHMRC Research Fellowship


Title of research award: Research Fellowship

Lay Description (from application):

No available Lay Description

Research achievements (from final report):

Identification of fish parathyroid hormone (PTH), a potential new treatment for osteoporosis in humans. Human
PTH is being used currently to treat osteoporosis but it is injected sub-cutaneously and the toxicology studies in
rats were stopped at 18 months as the animals developed osteosarcomas. This resulted in the clinical trials being
halted and the Federal Drug Adminstration in the US limiting the length of treatment to 18 months. So the aim is
to develop an agent that can be used orally and that has less side-effects. In the last 2 years Fish PTH has been
shown to be active in mammalian bone cells and to form new bone in a rat model of bone formation. So the next
steps are to further test in a rat model of osteoporosis and to examine its toxicology. These experiments are time-
consuming and expensive to complete. If this research program is successful then fish PTH could be a new and
safer treatment for osteoporosis.

Expected future outcomes:

The development of new bone-forming agents based on fish PTH molecules, that can be used in humans to treat
osteoporosis. These agents would able to be adminstered orally and be free of the side-effects now found with
human PTH

Name of contact:      Assoc.Prof. Janine Danks
Email of contact:     j.danks@unimelb.edu.au
                           NHMRC Research Achievements - SUMMARY
Sir Charles Gairdner Hospital

Grant ID:     294402                                           Start Year:      2003
CIA Name:     Dr Scott G Wilson                                End Year:        2006
Main RFCD:    Quantitative Genetics                            Total funding:   $328,250.00
Admin Inst:   Sir Charles Gairdner Hospital                    Grant Type:      Standard Project Grant


Title of research award: Linkage disequilibrium mapping and positional cloning for gene identification in
osteoporotic families

Lay Description (from application):

Osteoporosis is a common chronic disease with associated pain, loss of function and death. Patients with the
disease commonly experience spine, hip or wrist fracture. Fracture of vertebrae may result in chronic back pain
and deformity. Respiratory and

Research achievements (from final report):

The aim was to identify disease-associated genes from linkage data on bone mineral density (BMD). We
previously completed genome scans of twins and families with a history of osteoporosis and identified regions for
study. First, we refined the support intervals and selected 2 linkages for study (1p36, 3p21). We characterised
genes within the regions using a bioinformatics approach and generated detailed lists of the candidate genes. We
defined haplotype tag SNPs (HT-SNPs) in 94 candidate genes and across the interval at 3p21 and genotyped these
creating a dense SNP map (~1,2 million genotypes). A significant association was defined with a SNP in a gene in
the 1p36 linkage region (BMD at the total hip (P = 0.023) and femoral neck (P = 0.008). The average reduction in
BMD was 3.4-4.1% for homozygous individuals. We replicated this finding in an independent population-based
cohort (Femoral neck BMD, P < 0.005; see Mullin, 2007)). In addition, we showed that a coding SNP (rs17563) in
the BMP4 gene, also under a linkage peak, is associated with total hip and intertrochanter BMD. Homozygotes
show a 3.1% difference in BMD at the hip site (Ramesh-Babu, 2004). We then demonstrated associations with
HT-SNP in three potentially interacting genes on 3p21, an acting binding protein (Femoral Neck BMD, P =
0.0001), a small GTPase (Femoral Neck BMD, p= 0.0004) and a nucleotide exchange factor (Femoral Neck
BMD, P = 0.0004). Finally, we replicated these associations in population-based cohorts, thus verifying the
findings (P = 0.02, 0.04, 0.04 respectively).

Expected future outcomes:

The three novel genes we have identified as associated with BMD within the 3p21 genomic region require further
study to determine the functional basis of the observed effect. The data resulting from this project provides new
tragets for the potential development of diagnositc and therapeutics options relating to low BMD and osteoporosis.

Name of contact:      Lynell Belardo
Email of contact:     Lynell.Belardo@health.wa.gov.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      343603                                             Start Year:      2005
CIA Name:      Dr Scott G Wilson                                  End Year:        2007
Main RFCD:     Quantitative Genetics                              Total funding:   $400,250.00
Admin Inst:    Sir Charles Gairdner Hospital                      Grant Type:      Standard Project Grant


Title of research award: Genetic regulation of hip geometry, structure and fracture

Lay Description (from application):

Osteoporotic hip fracture is common in the elderly and a major cause of hospitalization. Hip fracture may lead to
surgery, chronic reduced mobility, loss of function, institutionalization or death. The term osteoporosis covers a
heterogeneous syndrome including juvenile, secondary (e.g. corticosteroid induced) and postmenopausal
osteoporosis. This later broad grouping shows evidence of a strong familial association. Previous work has shown
that a family history of fracture increases the risk of fracture by more than four fold. Furthermore, studies in twins
have persistently shown that phenotypes such as bone mineral density (BMD), broadband ultrasound attenuation
of bone and hip structural indices are strongly inherited. This confirms a genetic basis for the disease in some
individuals. Community health in general has improved substantially in Australia in the past four decades and this
has resulted in increased longevity. In contrast, the incidence of hip fracture and the resulting drain on public
health funding continues to increase rapidly. Presently the cost of osteoporosis in Australia is $7.5 billion per
annum. Hip fracture accounts for the majority of these costs. Instituting effective prevention strategies is essential.
This project aims to contribute to one of Australia's National Research Pritoities by improving understanding
about the way in which inherited aspects of hip geometry and structure contribute to the hip fracture susceptibility.
We have successfully completed genome screen projects studying genetic linkage in the families to localize genes
regulating BMD in the past. However, BMD is only one of a number of relevant phenotypes. In relation to hip
fracture, geometry and structure are thought to be particularly important. In this project we will make use of
existing resources to advance studies of both genetic linkage and association to examine fundamental issues
related to hip facture.

Research achievements (from final report):

Osteoporotic hip fracture is common in the elderly and is a major cause of morbidity and mortality, the goal of
this project was to find genes that control hip structure, particularly those which are relevant to hip fracture. The
study used existing radiographs and dual x-ray absorptiometry (DXA) scans on a large cohort of women and
derived important new phenotypes on hip structure and geometry from these resources. That phenotype data was
then used in analyses with existing genetic data for these study subjects to identifying genes with a potential role
in the regulation of hip geometry and structure. We identified 13 discrete genomic regions that showed genetic
linkage to hip structure and geometry phenotypes. Furthermore, we identified 23 individual genes with replicated
evidence of statistically significant association with hip structure traits. These results assist in improving
knowledge and understanding of the genetic control of hip structure. The long-term goal of the research program
is to develop intervention strategies to reduce hip fracture incidence.

Expected future outcomes:

This data will enable targeted validation studies of the mechanisms involved in the genetic regulation of hip
structure and geometry. Although further replication and molecular biology studies are necessary to fully validate
the findings, some of the genes identified may be useful in the development of diagnositic and therapeutic
approaches for osteoporosis and osteopeania.

Name of contact:       Lynell Belardo
Email of contact:      Lynell.Belardo@health.wa.gov.au
                            NHMRC Research Achievements - SUMMARY
St. Vincent's Institute of Medical Research

Grant ID:      395512                                            Start Year:       2006
CIA Name:      Prof Michael W Parker                             End Year:         2008
Main RFCD:     Cellular Immunology                               Total funding:    $498,750.00
Admin Inst:    St. Vincent's Institute of Medical Research       Grant Type:       Standard Project Grant


Title of research award: Determining the structure of a soluble cytokine receptor complex

Lay Description (from application):

There is a pressing need to develop improved therapeutics to treat many forms of cancer and respiratory diseases.
This proposal concerns the biochemical investigation of a group of protein hormones and their associated
receptors that are implicated in blood cell cancers and for which current treatments are only partly effective . Our
work will focus on determining the 3-dimensional shape and function of this group of proteins in complex with
one another which will provide us with an understanding of how these proteins "communicate" with one another.
This information may provide a basis for the design of new drugs that can specifically block the activity of these
protein hormones, thereby providing new treatment possibilities for these blood cell cancers.

Research achievements (from final report):

We unravelled the 3D structure of a cell signalling receptor found on the surface of blood cells which, when
damaged, is responsible for diseases such as leukaemia and inflammatory diseases such as asthma and arthritis.
This discovery helps to explain, for the first time, how this receptor is activated and will form the springboard for
the development of new treatments.

Expected future outcomes:

To maximise the drug development opportunities of this discovery both Institutes involved in the discovery have
recently signed an agreement with biopharmaceutical company CSL Limited. Under the agreement the Institutes
will work with CSL to discover and develop new therapeutic antibodies to treat certain types of leukaemia and
inflammatory diseases.

Name of contact:       Professor Michael Parker
Email of contact:      mparker@svi.edu.au
                           NHMRC Research Achievements - SUMMARY
University of Adelaide

Grant ID:     207701                                           Start Year:      2002
CIA Name:     Prof Nick L Fazzalari                            End Year:        2004
Main RFCD:    Orthopaedics                                     Total funding:   $317,640.00
Admin Inst:   University of Adelaide                           Grant Type:      Standard Project Grant


Title of research award: Molecular deteriminats of bone remodelling in the bone microenvironment

Lay Description (from application):

There is little information regarding the expression of specific molecules in human bone tissue or their role in
skeletal disease. The process of bone remodelling is fundamental for the maintenance of skeletal integrity. Our
understanding of the molecular signalling involved in activating bone remodelling is principally derived from
tissue culture and animal experiments. We will study human cancellous bone samples donated by patients
undergoing surgery, and with the consent of the next-of-kin, taken at autopsy. These molecular and
histomorphometric studies will determine whether the understanding derived from tissue culture and animal
experiments is consistent with associations demonstrable in the human cancellous bone microenvironment. The
elucidation of the molecular signalling in the human bone microenvironment is essential for the effective
diagnosis and treatment of bone disease. Recently reported studies have shown very persuasively that fatigue
microdamage accumulates in the skeleton and is targeted for repair by remodelling. Our preliminary data shows
that microcrack length is positively correlated with IL-11 mRNA gene expression. We will further investigate
mRNA gene expression of a number of cytokines involved in bone cell signalling and their association with the
level of microdamage in the bone. Using a animal model of controlled bone microdamage induction we will seek
to determine the bone remodelling causal relationship between microdamage and cytokine signalling.
Furthermore, the cellular and molecular mechanisms that lead to trabecular structures are not well understood.
These studies will provide new insight into the processes that determine trabecular structures. This project will
investigate these mechanisms and increase our understanding of bone cell function, essential for diagnosis and
design of rational treatment for bone diseases.

Research achievements (from final report):

In this project, we have investigated the expression of key regulatory molecules of bone renewal in the
microenvironment of trabecular bone samples from patients who have suffered osteoporotic fragility fractures and
osteoarthritis. We have combined investigation of gene expression in human bone with measurement of tissue
morphology (histomorphometry), to investigate links between molecules that participate in bone renewal. Bone
samples were taken from patients undergoing hip replacement for a fragility fracture of the femur and total hip
replacement for osteoarthritis. We have found that the expression of a number of key genes that control bone
renewal, RANK and IL-6 mRNA and RANKL/OPG mRNA ratio, was significantly elevated in the osteoporotic
fracture group compared to an age-matched control group. These data suggest a relative increase in the expression
of the molecular promoters of osteoclast formation (cells that remove bone) and activity in osteoporotic fragility
fracture bone, which may lead to the imbalance between bone formation and removal associated with fragility
fracture. When the same bone samples used for molecular analysis were examined by histomorphometry, bone
formation parameters were significantly reduced in the fracture patients compared to controls. These data are
important because they are among the first to draw attention to a reduction in bone formation, rather than
increased bone removal, in association with osteoporotic fragility fractures. In additional work, we have
performed microarray experiments, comparing gene expression in osteoporosis and osteoarthritis bone samples. A
number of different classes of genes have been identified as being up-regulated in osteoporosis compared to
osteoarthritis, which is consistent with the reduced bone mass seen in osteoporosis compared to osteoarthritis.
This project grant increased our understanding of the mechanisms of bone renewal and potentially identified new
tragets for novel drug development.

Expected future outcomes:
                            NHMRC Research Achievements - SUMMARY

Our studies have shown that the disregulation of bone cell signals and their relationship to bone tissue properties is
a potential determinant of fragility fracture risk. The elucidation of the mechanism of bone renewal identifies
potential new tragets for novel drug development.

Name of contact:       Nick Fazzalari
Email of contact:      nick.fazzalari@imvs.sa.gov.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      157970                                             Start Year:       2001
CIA Name:      Prof Leslie G Cleland                              End Year:         2005
Main RFCD:     Rheumatology and Arthritis                         Total funding:    $450,000.00
Admin Inst:    University of Adelaide                             Grant Type:       Extended

Title of research award: Dietary n-3 fats and outcomes in early-onset rheumatoid arthritis
Lay Description (from application):
There is considerable evidence that positive health benefits flow from increasing the dietary intake of omega-3
polyunsaturated fats. Benefits are seen in rheumatoid arthritis, other inflammatory disorders and heart disease.
Previous studies of rheumatoid arthritis and dietary omega-3 fats had a common design which probably reduced
the magnitude of the beneficial dietary effects. Therefore, a 'second generation' study is needed which addresses
these common design issues in order to establish optimal conditions for the use of dietary omega-3 fats in therapy
for rheumatoid arthritis. The current proposal will address the previous design shortcomings by changing the
background diet, measuring functional disability and joint damage as well as symptoms, starting treatment in early
disease before joint damage has occurred, and by regulating concurrent drug use. The study will also evaluate a
novel blood test that indicates the effect of advice to increase dietary omega-3 fats upon omega-3 nutritional
status. If this nutritional index correlates with more favourable outcomes, a base will have been established for
guiding treatment with omega-3 fats in routine clinical situations. This study is important because dietary
treatment in rheumatoid arthritis: (a) offers sufferers with rheumatoid arthritis a more active role in the life long
management of their disease. (b) has no on-going cost to the government health budget, and in fact, has the
potential to decrease treatment costs in rheumatoid arthritis considerably (c) has wider applicability, e.g. for
prevention and treatment of other inflammatory conditions and heart disease (d) needs to be tested with modern
treatment protocols that involve multiple therapies started early in the course of rheumatoid arthritis, before
irreversible impairment and disability has occurred (e) requires a nutritional index to guide treatment (f) must be
evidence based.

Research achievements (from final report):

The project shows a way in which rheumatoid arthritis can be treated more effectively. The approach is multi-
factorial and involves systems for oearly referral of recent onset polyarthritis o triage based on perusal of referrals
(allows priority early assessment and early treatment of suitable cases) o use of combinations of inexpensive
treatments in combination (with avoidance of oral steroids) o drug choices, adjustments in dose and substitutions
according to predefined rules (allows orderly, reproducible application of treatments) o proforma assessment of
joints and blood tests (triggers dose adjustments when disease is active) o documentation of unwanted effects and
reasons for treatment withdrawals (allows safety to be assessed). Against this background, the value, as a
component of the program, of fish oil, in an anti-inflammatory dose, has been has been assessed. The overall
results show that treatment of patients with combination therapy according to the rules, achieves favourably
results safely (remission rate 50%, good responses in 85% at 12 months, sustained to at least 3 years, no serious
drug related unwanted events). In patients taking fish oil regularly results were especially favourable (remission
rates 70%). In these patients compared to those not taking fish oil, there was a significant reduction in disability,
composite scores of disease activity, tender joint counts, discretionary 'NSAID' use and multiple indicators of risk
for serious cardiovascular events. The project has allowed the Early Arthritis Clinic approach and procedures to
become part of routine practice and ongoing observations will allow longer term outcomes to be monitored and
refinements made.

Expected future outcomes:
The program sets a new standard for treatment of rheumatoid arthritis (RA). Future directions include the
development of a computer-aided clinical assessment and decision support tool which will guide practitioners
through procedures needed to assess disease activity, to monitor for unwanted drug effects and to prescribe drugs
safely according to protocol.

Name of contact:       Professor Leslie Cleland
Email of contact:      lcleland@mail.rah.sa.gov.au
                           NHMRC Research Achievements - SUMMARY

Grant ID:       250301                                            Start Year:      2003
CIA Name: Prof Nick L Fazzalari                                   End Year:        2005
Main RFCD: Orthopaedics                                           Total funding: $409,000.00
Admin Inst: University of Adelaide                                Grant Type: Standard Project Grant
Title of research award: Interrelationships between the disc and bone of lumbar spinal segments
Lay Description (from application):
The cause of back pain due to osteoarthritis, osteoporotic vertebral crush fracture, and ageing is poorly
understood. Vertebral deformity, intervertebral disc disorganisation, and change to vertebral bone structure are
features associated with degeneration of the spine and with back pain. Degenerative disc disease is one of the
major causes of back symptoms and is believed to be associated with degeneration of the spine. Spinal
degeneration includes disc degeneration, facet joint osteoarthritis, compromised vertebral body bone quality,
muscle and ligament alterations. It is assumed that these changes result in increased or abnormal spine motion and
modified load distribution across the spinal joint. It has been found that with age, there is increased
disorganisation of the intervertebral disc and decreased quality of vertebral cancellous bone. However, bones with
the same density within the range of normal subjects, can show selective loss of bone structure and reduced load-
bearing capacities of these vertebrae. An important concept here is that even for a given bone mass, fracture risk
increases with age, supporting the view that there is a component of bone fragility that is independent of mass.
Increased bone fragility may be associated with compromised cancellous bone structure. While the relationship
between disc degeneration and changes in vertebral bone is commonly invoked, the mechanisms of this
relationship have largely been overlooked, with age changes given more attention. However, it may be that
intervertebral disc disorganisation modulates age-related bone changes within the spine. Disc degeneration may
influence trabecular bone responses before changes with age put the patient at risk of vertebral crush fracture. We
propose that the mature disc cannot effectively regenerate after damage, and thus responses to disc damage will be
more readily observed in vertebral bone architecture than in the disc.

Research achievements (from final report):

We have developed and implemented a novel MRI protocol to measure the water content of the intervertebral
discs in the human spine. This protocol is breaking new ground in that it provides a new clinical tool to measure
the water content of the intervertebral disc of patients with back pain. We have been able to show that the MRI
scans are reliable and reprobucible. Until the development of this technique, assessing the amount of water in the
intervertebral disc has been based on the subjective interpretation of an MRI image by a radiologist. There are few
studies of this nature that have been reported and a patent application is pending. In addition, this study has
provided a novel perspective of the bone in the spine. The thickness of the bone wall that surrounds the spongy
bone structure in the vertebral body was thicker in the front of the vertebra than the back of the vertebra,
suggesting that the bone wall in the front of the vertebra has to support a greater load than the back wall of the
vertebra. Combined with the data we have on the deformation of the vertebral body bone wall under load and how
the load is transmitted through the spongy bone in the vertebral body we have a unique insight into vertebral body
mechanics. This places us at the forefront of understanding the mechanism of vertebral body fracture where the
patient has fragile bones. The study has enabled us to better understand the relationship between the intervertebal
disc and the vertebral body bone. These unique data from the human spine have not been previously reported and
hold significant potential to understand bone quality factors that ultimately determine bone strength and what
factors should be the target of treatment.

Expected future outcomes:

This was a pioneering study using a multidisciplinary approach and our unique experience to elucidate the
mechanisms of spinal degeneration. The MRI protocol to measure the water content of the disc will provide a new
clinical tool to identify the presence of disc degeneration, monitor progression of disc degeneration and monitor
the efficacy of treatment of disc degeneration in patients.

Name of contact:      Nick Fazzalari
Email of contact:     nick.fazzalari@imvs.sa.gov.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      250344                                            Start Year:      2003
CIA Name:      Prof David M Findlay                              End Year:        2005
Main RFCD:     Orthopaedics                                      Total funding:   $345,000.00
Admin Inst:    University of Adelaide                            Grant Type:      Standard Project Grant


Title of research award: Mechanisms of periprosthetic bone loss

Lay Description (from application):

We will seek to address an important clinical problem in orthpaedics, namely the bone loss that commonly occurs
around joint replacement prostheses. Termed peri-prosthetic osteolysis (PO), this bone loss can result in the
loosening and ultimate failure and need for revision of the artificial joint components. PO is thought to be caused
by the body's reaction to wear particles generated from the articulating surface of the prosthesis. However, it has
not previously been possible to accurately explore the relationship between prothesis wear and PO, or the
progression of PO, because of a lack of techniques to image and measure the volume of PO around metal
prosthesis components. We have developed a means to accurately and reproducibly measure the volume of bone
loss, using CT, and will do so longitudinally in joint replacement patients to obtain the first information about the
progression of PO. New computer based methods will be used concurrently to relate prosthesis wear and
migration parameters to PO. Patients who come to surgery for replacement of failed prostheses will be
investigated further by analysis of the tissues involved in the bone loss around prostheses. Basic science
experiments will seek to understand the underlying causes of PO and the findings will be important in interpreting
the clinical results. An animal model will be used to seek approaches to inhibiting the pathological response to
wear particles. The significance of these studies is that they will lead to improved outcomes for joint replacement
patients, increasing the interval to revision surgery, which is both extremely costly and brings an attendant
morbidity and mortality.

Research achievements (from final report):

Peri-prosthetic osteolysis often limits the lifespan of total hip replacement implants. Therefore, the aim of this
project was to investigate peri-prosthetic bone loss, firstly by developing new imaging modalities and secondly by
identifying the molecular mechanisms responsible for this process. We made great progress towards these goals,
measuring in the same patient implant wear and migration and, for the first time, the progression of osteolysis. In
patients who required revision surgery, we analysed tissue taken from defined sites adjacent to osteolytic lesions
and found important relationships between particle accumulation in the tissues, the cell types present, and the
molecular species that are potentially causally involved in the pathological bone loss. These cytokines, such as
TNF and RANK ligand, were found in separate experiments to potentiate osteoclast formation and activity. This
work has therefore laid a strong basis for a new means of monitoring hip replacement patients and for
understanding (and therfore potentially treating) the cell and molecular basis for the bone loss that often occurs
around prostheses.

Expected future outcomes:

As stated, this work has therefore laid a strong basis for a new means of monitoring hip replacement patients,
which has been anabled by our development of a means to accurately quantitate osteolysis around medium to long
term hip replacements. The basic science part of the work may lead to new treatments for this bone loss.

Name of contact:       David Findlay
Email of contact:      david.findlay@adelaide.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      250411                                            Start Year:       2003
CIA Name:      Prof Leslie G Cleland                             End Year:         2005
Main RFCD:     Orthopaedics                                      Total funding:    $0.00
Admin Inst:    University of Adelaide                            Grant Type:       Standard Project Grant


Title of research award: Effect of lipid mediators and dietary fats in bone remodeling

Lay Description (from application):

Osteoporosis in a major public health problem which directly affects about 10% of the population, which is
currently around 2 million Australians. With aging of the population, it is projected that this proportion will
increase to more than 13% over the next 20 years. When it is considered that the direct hospital and residential
care costs attributable to osteoporotic fractures currently approaches $2 billion per annum, low-cost interventions
for increasing bone strength which are easily applied to the elderly population have enormous potential for health
benefits in Australia. Thus study will examine the effects of dietary omega-3 fats, of the kind found in fish and
fish oil, on the biology of bone metabolism and on bone strength. The results will provide information which may
be used in developing simple drug or dietary strategies for large-scale use for increasing bone mass and strength in
the elderly population. A strength of the study arises from the combination of research expertise in (a) dietary fats,
and (b) molecular biology of bone cells, and (c) animal models of bone metabolism which are amenable to dietary
interventions. This combination is unique, but builds on well established systems which hitherto have existed in
separate research paradigms. The Chief Investigator has considerable experience in development of diets enriched
in omega-3 fats which are practical and suitable for daily use on a long-term basis. This adds considerably to the
potential significance of the outcomes because, if favourable effects of omega-3 fats are observed and are
characterised with regard to mechanisms, the results can be rapidly translated into large-scale clinical use.

Research achievements (from final report):

This work follows a report that fish oil (mixed with evening primrose oil) could prevent bone loss in the elderly.
We examined this issue using dietary fish oil in a well characterised rat model of post-menopausal bone loss. The
results indicated that dietary fish oil had a modest positive effect on bone formation, but no effect on bone loss in
this experimental system.

Expected future outcomes:

Dietary fish oil has positive effects for heart disease and inflammatory conditions such as rheumatoid arthritis.
However, this study provided support for only a modest effect on bone formation in an animal model. If this were
to be pursued it would require a large clinical trial in the elderly.

Name of contact:       Professor Les Cleland
Email of contact:      leslie.cleland@health.sa.gov.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      250426                                             Start Year:      2003
CIA Name:      A/Pr Graham Mayrhofer                              End Year:        2005
Main RFCD:     Autoimmunity                                       Total funding:   $450,000.00
Admin Inst:    University of Adelaide                             Grant Type:      Standard Project Grant


Title of research award: The immunological microenvironment in the synovium during experimental
polyarthritis in the rat

Lay Description (from application):

In this project, we aim to understand the process by which some forms of arthritis, as exemplified by rheumatoid
arthritis (RA), cause inflammation and destruction of multiple joints. Such forms of arthritis are referred to
collectively as "polyarthritis". There is a strong evidence that RA has an immunological basis and that abnormal
recognition of components of the joints by T lymphocytes orchestrates the inflammation that is characteristic of
the disease. We believe that dispersal of disease-causing activated T lymphocytes in the blood accounts for the
involvement of many joints. We have used a model of polyarthritis in rats to study the nature of the activated T
lymphocytes, where they come from, how they are delivered to the blood stream and how they enter the joints.
This project focuses on the crucial tissues that line the joints. We want to understand how the disease-causing
activated T cells cause inflammation and how the immune system reacts to restrain them. We can undertake this
work because we have developed three unique tools. Firstly, we can transfer arthritis with activated T
lymphocytes and, therefore, study their behavior in an otherwise normal body. In this way, we can see how the
body responds to the presence of disease causing cells. Secondly, we have introduced a genetic "marker", which is
essential if one wishes to distinguish the separate activities of the "donor' and "host" cells. Thirdly, we can collect
cells from the diseased paws, allowing us to examine their activities in vitro as well as in vivo. This model offers
the opportunity to study the activities of the disease-causing cells and to identify points at which the disease cycle
can be broken. It will allow us to design and/or test new treatments aimed at these points.

Research achievements (from final report):

This project aimed to achieve a better understanding of the disease process that causes inflammation and joint
destruction in diseases such as rheumatoid arthritis. The work was undertaken in an animal model because this
allows syudy of the very early events and because it allows experimental interventions that are not possible in
humans. Rheumatoid arthritis is believed to result from an attck by the immune system on components of the joint
linings (synovium). In the model, we were able to study the part of the disease that is due to infiltration of the
synovium with T lymphocytes. We found that disease causing T cells localise selectively in synovium and
proliferate there. This was shown by transferring genetically marked cells from donors that have arthritis to
normal recipients and then examining both host- and donor-derived cells in the synovium. We found that the
period of proliferation was limited and that continuation of the disease was dependent on a continuous supply of
new T cells. This suggests that the rheumatoid process may not be confined to the joints and that the seat of
production of disease causing T cells may lie outside of the joints. We have also studied another key player in the
disease process. The dendritic cell is essential to activate T cells. We have characterised the dendritic cells in
normal and arthritic synovium. This work has applications for other forms of inflammatory diseases that involve
self-reactive T cells.

Expected future outcomes:

Understanding the dynamics of T cells and dendritic cells in synovium should lead to the identification of points
in the disease process that are tragets for new therapies.

Name of contact:       Graham Mayrhofer
Email of contact:      graham.mayrhofer@adelaide.edu.au
                           NHMRC Research Achievements - SUMMARY

Grant ID:      219305                                           Start Year:      2003
CIA Name:      Prof Nick L Fazzalari                            End Year:        2006
Main RFCD:     Orthopaedics                                     Total funding:   $262,500.00
Admin Inst:    University of Adelaide                           Grant Type:      Research Into Ageing


Title of research award: Healthy Ageing Research Grant

Lay Description (from application):

No available Lay Description

Research achievements (from final report):

Osteoarthritis is the most prevalent musculoskeletal disease. The most pressing healthcare need for the majority of
individuals with osteoarthritis is non-operative care, to help relieve symptoms, improve function, and slow disease
progression. Essential for effective non-operative care is the development of tools to enable the early diagnosis,
and monitoring of treatments, together with new insight into the molecular mechanisms that lead to primary
osteoarthritis, which can provide new opportunities for the development of effective drug therapies. New patient
management and treatment strategies will arise from a better understand of the pathogenesis of this prevalent
disease. Associate Professor Fazzalari's research team has used microarray based gene expression profiling of
bone from patients with hip osteoarthritis to show systemic changes to the skeleton that likely predispose
individuals to the disease. Though joint cartilage degeneration is a hallmark sign of osteoarthritis, in the past 50
years cartilage researchers have made little progress to develop treatments for the many patients with
osteoarthritis. Novel Wnt and TGFβ signalling pathway components, among others, have been identified that
promise new insight into osteoarthritis disease mechanisms and potentially therapeutic intervention. Researchers
are currently exploring the role that these genes have in altered bone structure seen in osteoarthritis and are also
using the identified genes to develop a diagnostic screening test for osteoarthritis. This research program will
provide essential new understanding both for early diagnosis and monitoring the effect of treatments or changes in
patient lifestyle that may delay the progression to severe joint degeneration, or prevent the disease.

Expected future outcomes:

We are working to develop a genetic screening test to identify individulas at risk of osteoarthritis. In addition,
seeking to understand the functional role of genes we have identified as being linked to the onset and progression
of osteoarthritis. This understanding will provide apportunities to develop new treatments to prevent or slow the
progression of osteoarthritis.

Name of contact:      Nick Fazzalari
Email of contact:     nick.fazzalari@imvs.sa.gov.au
                           NHMRC Research Achievements - SUMMARY

Grant ID:      299031                                           Start Year:      2004
CIA Name:      Dr Gerald J Atkins                               End Year:        2006
Main RFCD:     Orthopaedics                                     Total funding:   $429,450.00
Admin Inst:    University of Adelaide                           Grant Type:      Standard Project Grant


Title of research award: Relationship between human osteoblasts and haemopoietic cells in bone remodelling

Lay Description (from application):

Bone diseases, such as osteoporosis and osteoarthritis, currently afflict more than 4 million Australians. These
diseases are characterised by abnormal bone remodelling, which can result in a net loss of bone (for example, in
osteoporosis) or abnormal bone structure (for example, in osteoarthritis). We are seeking to better understand the
factors that regulate bone remodelling, and particularly the cells involved in this process. Physiological bone
remodelling results from the intimate collaboration between osteoblasts and osteoclasts. Osteoblasts stimulate the
formation of osteoclasts and also produce new bone at resporption sites. However, the way that the same type of
cell can perform both these tasks, is not clear. Our studies are designed to increase our understanding of the
development of human osteoblasts and of the factors that cause them to be sequentially pro-osteoclastic and then
pro-osteogenic. We believe that an important factor in this process is vitamin D and we will test the hypothesis
that this molecule is produced in bone and acts locally to regulate bone turnover.

Research achievements (from final report):

The aims of this proposal were: 1. To further define the link between the osteoblast differentiation state and the
formation of osteoclasts in response to various factors that act on the skeleton; 2. To further characterise the
signals between, and the influences of, haemopoietic cells and osteoblasts during both osteoclastogenesis and
osteogenesis; 3. To define the role of 1,25(OH)2vitamin D3 metabolism in human bone cell biology. This has
been a highly successful and productive period of research, resulting to date in 11 publications including two book
chapters. At least 6 further publications describing work encompassed in this project are in preparation. We have
succeeded in obtaining significant new insight into human osteoblast biology with respect to their production of
osteoclast activating factors, their response to osteoclast derived factors, and the way in which they differentiate
into mineral producing cells and further, into mature osteocytes. We have established that the skeleton is an
intracrine organ for vitamin D metabolism, effectively describing a paradigm shift in this field. This has important
implications for the interpretation of the diagnostic indicator of vitamin D status, namely, the serum 25-
hydroxyvitamin D level. We have characterised a number of pathways whereby osteoblast differentiation is
modulated by proinflammatory signals deriving from both haemopoietic cells and from osteoblasts themselves,
which is likely to be important in bone repair and in diseases of bone inflammation, such as rheumatoid arthritis
and osteoporosis. We have also established an effective model, with which to examine the mechanism of action of
anabolic therapeutics for the treatment of osteoporosis. Our results have direct implications for the treatment of a
number of bone degenerative diseases.

Expected future outcomes:

This project has formed the basis of two further major projects, examining the role in bone of the inflammtory
cytokine TWEAK, and the effect on bone cells of wear particles derived from orthopaedic prostheses. We have
also established important collaborations with international companies to investigate the modes of action of
skeletal therapeutics on human bone cells in vitro.

Name of contact:      Dr. Gerald Atkins
Email of contact:     gerald.atkins@adelaide.edu.au
                           NHMRC Research Achievements - SUMMARY
Grant ID:     298993                                           Start Year:      2005
CIA Name:     Prof Antonio Ferrante                            End Year:        2007
Main RFCD:    Medical Biochemistry: Lipids                     Total funding:   $494,250.00
Admin Inst:   University of Adelaide                           Grant Type:      Standard Project Grant


Title of research award: Polyunsaturated fatty acids mimetics with anti-inflammatory properties

Lay Description (from application):

Autoimmune diseases are responsible for a high incidence of morbidity and mortality in our community.
Immunosuppressive drugs/anti-inflammatory agents have played important roles in treatment of these diseases as
well as in helping to prevent rejection of transplanted tissues/organs. There is an ongoing search by the medical
community for better immunosuppressive drugs and agents for use for these purposes. Based on studies conducted
in the last few years, we have partially identified structural elements on polyunsatrated fatty acids (PUFA) which
are responsible for specific biological functions. Using this information, we have synthesized a large panel of
previously unavailable PUFA which we can use to target T lymphocytes and drive the biological activity of these
compounds, preferentially towards immunosuppression. By conducting the research outlined in this project, we
are likely to either identify a lead immunosuppressive compound or generate new information for further synthesis
of PUFA-based compounds for further examination as potential immunosuppressive agents.

Research achievements (from final report):

The studies have identified a unique property which can be bestowed on polyunsaturated fatty acids to make them
more potent and selective in suppressing uncontrolled pathways in inflammatory diseases which cause substantial
morbidity and mortality in our community. this includes arthritis, asthma, allergy etc. Our research group has
desgined new polyunsaturated fats which act on the immune system in the test tube and translated these findings
to experimental models of the human diseases. The fatty acids were able to block the immunological pathways
which endanger the body when these inflammatory reactions take place. This has not been described previously.
Our research has defined both the cells and the molecules which are targeted by the novel fats. When the
hormones of the immune system were investigated both at the protein and gene level, it became evident that the
type and levels expressed correlated with the protection against inflammation.

Expected future outcomes:

We have identified a fatty acid which has unique anti-inflammatory properties so that future work could use this
prototype to developing anti-inflammatory, anti-infective and anti-cancer agents. This technology has now been
partly commercialised and the group is cautiously optomistic that some of the fatty acids will become useful
therapeutic agents.

Name of contact:      Prof Antonio Ferrante
Email of contact:     antonio.ferrante@adelaide.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      399168                                            Start Year:      2006
CIA Name:      Prof David M Findlay                              End Year:        2008
Main RFCD:     Orthopaedics                                      Total funding:   $505,000.00
Admin Inst:    University of Adelaide                            Grant Type:      Standard Project Grant


Title of research award: Impaired bone remodelling leads to failure of orthopaedic prostheses

Lay Description (from application):

The failure of bone prostheses is becoming a major health problem. More than 26,000 hip, and an equal number of
knee, replacements were performed in Australia in 2002 with the number increasing between 5%-10% each year
for the previous 10 years. Disturbingly, the incidence of revision hip surgery in Australia is now more than 15%,
meaning that, despite the impressive success of joint replacement surgery, a significant number of arthroplasties
fail. It is becoming more common for young, active individuals to receive joint replacement surgery to improve
their quality of life. This, combined with increasing life expectancy, and the known higher rate of failure of joint
replacements in younger patients, means that the morbidity of a failed replacement, and the mobidity and
associated mortality of revision surgery, will become an increasingly important health issue, with a major impact
upon health budgets. The overwhelming majority of hip and knee prostheses have metal or ceramic on
polyethylene bearing surfaces. It is now apparent that most implants fail due to bone loss around them leading to
loosening, and evidence is accumulating that polyethylene wear particles are a major contributing factor to this
process. It is therefore vital that we obtain better understanding of the causes of implant failure in order to extend
the life of these implants and this project is designed to do so.

Research achievements (from final report):

The aim of this project was to understand the reasons for the eventual loss of bone that is observed around
artificial joints. We found previously that polyethylene (PE) particles generated in the joint by wear of the
articulating surface of the prostheses were strongly related to the extent and rate of bone loss. In this project, we
have shown that where PE particles accumulate in the joint tissues, there is an accompanying accumulation of
giant cells, which engulf the particles and also molecules that are involved in the physiological resorption of bone.
These molecules include RANK, RANKL, OSCAR, TWEAK and TNF. In further investigating the action of
these molecules on bone cells, we have found that TWEAK reduces the ability of osteoblasts to make bone. To
examine more directly the mechanism, by which PE particles interact wirth osteoblasts and osteoclasts, we have
obtained PE particles similar to those produced as prostheses begin to wear. We have devised a novel method of
exposing cells to these particles by including them with cells in a gel material. We have found that osteoblasts
behave very differently in the presence of PE particles. Specifically, they produce less of the substances required
to make bone and more of the molecules that promote osteoclast formation. In addition to this, we have found that
PE particles can directly increase the production of osteoclasts from their precursor cells.

Expected future outcomes:

Our findings show a direct role for PE particles in the bone loss around articulating orthopaedic implants and draw
attention to the need for new bearing materials with better wear characteristics. They also provide clues for
preventing this bone loss, while at the same time encouraging continued bone formation around implants.

Name of contact:       David Findlay
Email of contact:      david.findlay@adelaide.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:        399305                                             Start Year:      2006
CIA Name: Prof Nick L Fazzalari                                     End Year:        2008
Main RFCD: Orthopaedics                                             Total funding: $438,125.00
Admin Inst: University of Adelaide                                  Grant Type: Standard Project Grant
Title of research award: Intrinsic bone qualitites in fragility fracture patients: mass, microarchitecture,
mineralization and damage accumulation
Lay Description (from application):
Osteoporosis drug therapies have been associated with a significant reduction in fragility fracture. Patients
receiving osteoporosis drugs, which have different effects on BMD, may have similar reductions in fractures.
Furthermore, patients with fragility fractures may have abnormalities in bone structural and material properties.
Changes to the process of bone renewal, due to drug therapy, may explain why fracture risk decreases where no
detectable change to the structure of bone has been detected. It has also been shown that when bone renewal is
suppressed microdamage accumulates in bone tissue, leading to reduced bone toughness. The toughness of bone is
of primary importance in relation to fragility fractures, and it has been shown that the fatigue strength and fracture
toughness (work to fracture) reduce considerably with age. This proposed study would seek to elucidate the role of
bone tissue-level properties in determining bone quality for human subjects: patients with fragility hip fractures on
no osteoporosis drugs therapy, hip fracture patients on osteoporosis drugs therapies, and normal age- and sex-
matched individuals. Our laboratory has extensive experience in the analysis of the structure of human bone
tissue. Recently, we have developed novel and unique techniques to assess bone quality, using micro-CT,
backscatter SEM imaging, confocal microscopy and immunohistochemistry. This multifaceted study will identify
at the bone tissue-level the structural mechanisms (micro-architecture, mineralisation, and microscopic cracking)
that are indicative of the efficacy of fragility fracture drugs. Better understanding of the mechanisms by which
bones are less likely to fracture will enable better targeting of osteoporosis drug therapy to individuals at risk of
fragility fracture.

Research achievements (from final report):
Fragility fracture risk is strongly dependent upon skeletal strength. Low bone mass is not the sole predictor of loss
of bone strength. Bone strength is determined by a number of inter-related structural and material components,
collectively constituting bone quality. We have undertaken complementary investigations of bone structure (how
bone is arranged in 3D space), bone mineralisation (how soft or brittle the bone is), and bone microdamage
accumulation (how many microscopic cracks are present in the bone) on bone specimens from the femur from
patients with fragility hip fractures that were not/were receiving osteoporosis drug therapy and skeletally normal
individuals (non-fracture controls). Measurements of trabecular bone volume (3D bone mass) and bone
microarchitecture do not discriminate hip fracture patients from controls. However, bone from hip fracture
patients is less mineralised and contains more unrepaired microdamage (damage is repaired/removed by bone
turnover) compared to control individuals. Hip fracture patients that were receiving osteoporosis drug therapies
prior to fracture, show a different bone mineralisation profile compared to the fracture patients not on therapy and
controls. Our data demonstrate that the effect on bone of osteoporosis drug therapies, and hence reduction of
secondary fragility fracture, may differ on an individual patient basis. Our finding of altered bone mineralisation
profiles for hip fracture patients that were not/were receiving osteoporosis drug therapies and non-fracture controls
implicates the involvement of bone turnover in determining bone material quality, and hence bone strength. This
project has delivered novel material property data for fragility hip fracture patients and non-fracture individuals
representative of the Australian population. These data together with other bone quality measures may be of
central importance in defining individualised fracture risk assessment and tailorised treatment efficacy.

Expected future outcomes:
Currently prescribed osteoporosis drug therapies only reduce the risk of fracture by approximately 50%. Novel
bone quality data obtained for fragility fracture patients arising from this project has identified individualised
responses to osteoporosis drug therapy. Future preventative treatment approaches for primary and secondary
fragility fracture must be considered on an individualised basis.

Name of contact:       Prof Nick Fazzalari
Email of contact:      nick.fazzalari@imvs.sa.gov.au
                           NHMRC Research Achievements - SUMMARY
University of Canberra

Grant ID:      303404                                           Start Year:      2004
CIA Name:      A/Pr Surendran Mahalingam                        End Year:        2007
Main RFCD:     Infectious Diseases                              Total funding:   $330,375.00
Admin Inst:    University of Canberra                           Grant Type:      New Investigator

Title of research award: A novel mouse model to investigate the mechanisms of viral induced arthritis.
Lay Description (from application):
We have developed a novel animal model by which to study arthritic disease caused by insect-transmitted viruses
known as arboviruses. The existence of this model and novel reagents provides an excellent opportunity to further
explore the basic mechanisms of infectious disease in a complete functioning animal, rather than specific cultured
cells. The study will use modern approaches in molecular and cellular biology to achieve this goal. The production
by our immune systems of soluble mediators (cytokines/chemokines) and antibodies is an overwhelming positive
aspect of our physiological response to infection by microbes. Protection from disease by these immune
compounds can happen naturally, or the body's ability to produce these factors can be exploited to our benefit via
the administration of vaccines. However, these factors can also be detrimental to the host contributing to severe
disease. For instance, work performed almost 40 years ago showed for the first time that under particular
conditions, antibodies against viruses can enhance infection, instead of inhibiting infection as normally seen. In
the intervening years work by scientists all over the world has associated "antibody-dependent enhancement"
(ADE) of infection to many types of viruses; ADE is even thought to be a risk factor to serious disease with
dengue virus, and has been shown in vitro for the AIDS virus and Ebola virus. We have recently discovered a
molecular mechanism which explains how antibody enhances viral infection in vitro. In studies on immune cells
infected with Ross River Virus (RRV) we found that infection helped by antibody resulted in the specific
disruption to the production of cellular chemicals which are toxic to viruses. Are these mechanisms of antibody-
enhanced infection also found in animals? Will such mode of infection cause enhanced disease and tissue
pathology (arthritis) in animals?

Research achievements (from final report):

Mosquito-borne alphaviruses causing arthritis are found in many parts of the world and include Sindbis virus, the
related Scandinavian Ockelbo virus, the African/Asian chikungunya virus, the African O'nyong-nyong virus, the
South American Mayaro virus, and the Australasian Barmah Forest and Ross River viruses (RRV). RRV is
endemic to Australia and New Guinea and is the aetiological agent of epidemic polyarthritis or RRV disease
(RRVD). There is a substantial gap in our knowledge on how viruses cause arthritis. Achievements: We have
accumulated a considerable body of evidence describing our model of viral-induced arthritis. In addition, we have
accumulated a considerable body of evidence describing the roles of cells and soluble mediators in our model. We
have unravelled the pathobiology of RRVD. The disease has been shown to be an infectious arthritis with
symptoms probably associated with immunopathological responses to virus persisting in joint macrophages. We
have shown that RRV can establish a persistent productive infection in macrophages despite the presence of
neutralising antibodies, a process probably also requiring modulation of type I IFN and antiviral responses.
Benefit: This study has laid the foundation for the new understanding of viral arthritis. The project has
significantly enhanced our understanding of the pathogenesis of virus-induced rheumatic disease which can
ultimately lead to improved therapies against these diseases.

Expected future outcomes:

The mechanims of disease is poorly understood. We have developed a novel animal model of disease by which to
study arthritic disease caused by viral infections. We will be able to identify and understand the pathophysiologic
mechanisms by which viral arthritis causes acute and chronic arthropathies.

Name of contact:      Suresh Mahalingam
Email of contact:     Suresh.Mahalingam@canberra.edu.au
                           NHMRC Research Achievements - SUMMARY

Grant ID:      303413                                          Start Year:      2004
CIA Name:      A/Pr Surendran Mahalingam                       End Year:        2008
Main RFCD:     Medical Virology                                Total funding:   $450,000.00
Admin Inst:    University of Canberra                          Grant Type:      Biomedical CDA


Title of research award: The mechanisms of alphavirus-induced arthritis using a novel animal model

Lay Description (from application):

No available Lay Description

Research achievements (from final report):

Mosquito-borne alphaviruses that cause arthritis are found in many parts of the world and include Sindbis virus,
the Scandinavian Ockelbo virus, the African/Asian Chikungunya virus, the African O'nyong-nyong virus, the
South American Mayaro virus and the Australasian Barmah Forest and Ross River viruses (RRV). RRV is
endemic to Australia and New Guinea and is the aetiological agent of epidemic polyarthritis or RRV disease
(RRVD). There is little known about how these viruses cause arthritis in humans. We have developed a mouse
model of viral-induced arthritis, where the arthritis symptoms observed in human disease are replicated in young
C57Bl/6 mice. We have also accumulated a considerable body of evidence about the roles of specific cells and
soluble mediators in the viral induction of arthritis, such as in RRVD. The disease symptoms are associated with
immunopathological responses in the host to the viral infection. Despite the presence of neutralising antibodies,
RRV establishes a persistent productive infection in macrophages in the joints and modifies the hosts' type I
interferon and other immune responses to the viral infection. Together, these explain the often prolonged duration
of symptoms in humans following infection with RRV. This study has laid the foundation for understanding the
pathogenesis of viral arthritis, which can provide vital information for the development of agents to treat the
disease and its symptoms in humans. The mouse model can also be used to test possible treatments.

Expected future outcomes:

We have developed a novel animal model of disease to study arthritic disease caused by viral infections. We are
using this model to identify the pathophysiologic mechanisms by which the viral infection causes acute and
chronic arthropathies and to test potential therapies to treat the arthritic symptoms.

Name of contact:      Suresh Mahalingam
Email of contact:     Suresh.Mahalingam@canberra.edu.au
                            NHMRC Research Achievements - SUMMARY
University of Melbourne

Grant ID:      145820                                            Start Year:      2001
CIA Name:      Prof Ego Seeman                                   End Year:        2003
Main RFCD:     Endocrinology                                     Total funding:   $195,000.00
Admin Inst:    University of Melbourne                           Grant Type:      Standard Project Grant


Title of research award: Apportioning deficits in bone size and density in women with fractures to growth or
ageing by studies in their daughters

Lay Description (from application):

Women fracture their bones because the bones are small and break easily and because the bones are thin or low in
denseness (very porous like a honey comb). This study is aimed at identifying why women with fractures have
small bones and why the bones are so porous. They may have these problems because they lost a lot of bone as
they get older or because growth was abnormal so the size of the bone didn't reach its potential size or because the
denseness of the bones didn't develop properly. The study will be carried out in women with spine or hip fractures
and their daughters. All participants will have bone densitometry, provide a 24 hour urine sample and a fasting
blood sample of 20 ml whole blood. Informed consent will be obtained from all participants. The bone density
scan is associated with radiation exposure of about 4 mSv, about one tenth of a chest x ray, temporary bruising
may follow taking blood. If we can understand the different ways osteoporosis can occur we can then start to
devise specific treatments tailored to the individual. Also if we can identify the causes of small bones and bone
thinness during growth it may be possible to correct some of these causes before the reduced growth and reduced
building of bone occurs. We might also prevent the thinning of bone by identifying and removing causes of bone
thinning.

Research achievements (from final report):

The aim of this study is to determine if the deficits in bone mass and size in women with spine or hip fractures are
growth-related (reduced bone accrual during growth), age-related (excessive bone loss), or a combination of the
two. Women with spine fractures have low bone density at the spine, which is likely due to reduced accrual during
growth, as the deficits in their daughters' bone density were about half that of their mother's. However, the lower
vertebral size in women with spine fractures is likely to occur during aging, as their daughters do not have deficits
in vertebral size. Women with hip fractures have larger femoral neck bone size, lower bone density and a thinner
bone. Daughter of women with hip fractures also had larger femoral neck bone size, but normal bone density and
normal bone thickness. Therefore, we infer that the larger bone size in women with hip fractures is growth-related,
but the reduction in bone density and thinning of the bone occurs during aging. Fragility fractures at the spine and
hip have their origins in both growth and aging. The results of this study should influence how osteoporosis is
viewed and the approach taken to research, prevent and treat osteoporosis. Approaches need to look beyond just
factors influencing bone density during aging, to also include factors that affect bone density during growth and
influence bone size and structure. The major shift appears to be from treatment in adulthood, to prevention and
risk assessment during both growth and aging.

Expected future outcomes:

The results of this study open new approaches to research into the pathogenesis and prevention of bone fragility.
Drug therapy may need to be different in persons with deficits due to low peak accrual versus those with excessive
bone loss. Approaches to the whole of the population during growth and aging are needed just as cardiovascular
disease prevention is increasingly focussed at children.

Name of contact:      Ego Seeman
Email of contact:     egos@unimelb.edu.au
                           NHMRC Research Achievements - SUMMARY

Grant ID:      208960                                           Start Year:      2002
CIA Name:      Prof Eleanor J Mackie                            End Year:        2003
Main RFCD:     Endocrinology                                    Total funding:   $322,500.00
Admin Inst:    University of Melbourne                          Grant Type:      Standard Project Grant


Title of research award: Th role of protease-activated receptor-2 in regulation of bone metabolism

Lay Description (from application):

Many diseases of bones, such as osteoporosis and delayed fracture repair, result from the abnormal function of
bone cells. Factors regulating bone cell function are, therefore, important in maintaining a healthy skeleton, as
well as in the skeleton's response to disease. We have recently demonstrated the presence of a receptor called
PAR-2 on bone-forming cells. We have also shown that activation of PAR-2 inhibits the development of bone-
resorbing cells (osteoclasts) in response to hormones. We plan to investigate the mechanism of this effect, as well
as to identify how PAR-2 activation modulates other responses of bone cells to hormones. Molecules that activate
PAR-2 are present in bone in certain disease situations, but it is not known what activates PAR-2 in bone under
normal conditions. We will identify physiological activators of PAR-2 within bone.

Research achievements (from final report):

Many diseases of bones, such as osteoporosis and delayed fracture repair, result from the abnormal function of
bone cells. Factors regulating bone cell function are, therefore, important in maintaining a healthy skeleton, as
well as in the skeleton's response to disease. We have demonstrated that a receptor called PAR-2 on bone-forming
cells (osteoblasts) inhibits the development of bone-resorbing cells (osteoclasts) in response to hormones.
Furthermore, we have demonstrated that PAR-2 exerts this effect through inhibition of expression of a number of
factors produced by osteoblasts that are necessary for osteoclast formation. We have shown that a number of
tissue proteases that activate PAR-2 are not expressed in the bone environment, and that one putative activator of
PAR-2 is not capable of activating it. These observations add substantiallyto our understanding of osteoclast
biology, and therefore to bone biology in general.

Expected future outcomes:

The observations made in this grant have led to ongoing studies on regulation of osteoclast function by proteases.
These and our future studies are likely to help in the development of improved therapeutic approaches to bone
disease.

Name of contact:      Professor Eleanor Mackie
Email of contact:     ejmackie@unimelb.edu.auYes
                           NHMRC Research Achievements - SUMMARY

Grant ID:      251575                                           Start Year:      2003
CIA Name:      Prof Eleanor J Mackie                            End Year:        2003
Main RFCD:     Endocrinology                                    Total funding:   $345,000.00
Admin Inst:    University of Melbourne                          Grant Type:      Standard Project Grant


Title of research award: Cellular responses to thrombin in skeletal pathology

Lay Description (from application):

Many diseases of bones, such as osteoporosis and delayed fracture repair, result from the abnormal function of
bone cells. Factors regulating bone cell function are, therefore, important in maintaining a healthy skeleton, as
well as in the skeleton's response to disease. The enzyme thrombin is involved in blood coagulation but also
causes bone cells to alter their behaviour. Thrombin stimulates proliferation of bone-forming cells and protects
them from premature death. Thrombin also stimulates the breakdown of bone. We will investigate how thrombin's
effects on bone cell behaviour influence the course of bone healing. We will also determine how thrombin
stimulates bone breakdown and increases survival of bone-forming cells. This study will contribute to the
understanding of how bone cells function in health and disease.

Research achievements (from final report):

Many diseases of bones, such as osteoporosis and delayed fracture repair, result from the abnormal function of
bone cells. Factors regulating bone cell function are, therefore, important in maintaining a healthy skeleton, as
well as in the skeleton's response to disease. The enzyme thrombin is involved in blood coagulation but also
causes bone cells to alter their behaviour. In this project we have demonstrated that the early stages of bone
healing occur abnormally in the absence of the major thrombin receptor found in bone (PAR-1). We have found
that thrombin stimulates formation of osteoclasts (bone-resorbing cells). We have also identified a signalling
pathway through which thrombin prevents the death of osteoblasts (bone-forming cells). These observations add
substantiallyto our understanding of the biology of bone growth, maintenance and repair.

Expected future outcomes:

The observations made in this grant have led to ongoing studies on regulation of osteoclast function by proteases.
These and our future studies are likely to help in the development of improved therapeutic approaches to bone
disease.

Name of contact:      Professor Eleanor Mackie
Email of contact:     ejmackie@unimelb.edu.auYes
                            NHMRC Research Achievements - SUMMARY

Grant ID:      3211                                             Start Year:      2000
CIA Name:      E/Pr Thomas Jack Martin                          End Year:        2004
Main RFCD:     Rheumatology and Arthritis                       Total funding:   $3,254,043.37
Admin Inst:    University of Melbourne                          Grant Type:      Program Grant


Title of research award: Humoral and local regulators of bone resorption and formation.

Lay Description (from application):

No available Lay Description

Research achievements (from final report):

Several new discoveries that help explain how hormones and products of the body's immune system work together
to control the formation and breakdown of bone. These findings are relevant to the understanding of how
osteoporosis develops and how treatments can be improved for that condition, aiming at fracture reduction in the
elderly. The research has identified the fact that treatments used for building new bone make use not only of the
bone-forming cells (osteoblasts), but also of the cells that break bone down (osteoclasts). This is resulting in
critical review of how the new bone-building treatment , using parathyroid hormone, can be combined with
available drug inhibitors of bone breakdown (bisphosphonates, SERM's). The research has led to improved
understanding of the mechanisms important in the spread of breast cancers to bone, and their growth there as
secondary cancers. In particular, the Program research has highlighted how the bone environment itself can
profoundly change the behaviour of cancer cells once they are located there. This is focussing attention onto new
approaches to the prevention and treatment of metastatic disease in bone.

Expected future outcomes:

The Program will lead to the identification of bone cell products that will change current thinking regarding the
prevention and treatment of osteoporosis, and approaches to drug treatments, particularly in the use of drug
combinations. The cancer metastasis research is likely to result in new ways of preventing and treating bone
metastases in breast cancer.

Name of contact:      T.J.Martin
Email of contact:     jmartin@svi.edu.au
                           NHMRC Research Achievements - SUMMARY

Grant ID:     114118                                           Start Year:      2000
CIA Name:     Prof John F Bateman                              End Year:        2004
Main RFCD:    Cellular Interactions (incl. Adhesion, Matrix, Cell Wall)         Total funding: $1,460,822.00
Admin Inst:   University of Melbourne                          Grant Type:      Research Fellowship


Title of research award: Molecular mechanisms of collagen matrix assembly in health and disease

Lay Description (from application):

This project studies the way the specific protein building blocks of tissues interact with each other to form the
complicated structural networks necessary for tissue growth, development and function. Specifically, we will
study collagens, the main structural proteins of the body. We will determine how they assemble with other
proteins to form the complex fibrils or "molecular ropes," which provide mechanical strength to tissues and create
the environment for cells to grow and develop in tissues such as bone, skin, cartilage and muscle. We will explore
the effect of collagen mutations, that occur in patients with inherited diseases of cartilage and muscle, on these
assembly processes. This will provide key information on the disease process, so that in the future new approaches
to diagnosis and therapy can be developed. The understanding we gain on the molecular basis of tissue structural
assembly from these studies will be of importance for understanding normal tissue growth and development, and
for the development of new biomaterials for therapeutic use.

Research achievements (from final report):

The research project studied the gene and protein defects in inherited cartilage, bone and muscle diseases. Our
studies described the mutations in collagen type X and collagen type II causing serious developmental defects in
cartilage and bone. This information is of importance in diagnosis and the development of intervention strategies
as well understanding how cartilage assembles and grows. Our collagen type X studies also disclosed new cellular
processes of quality control that has wide ramifications for understanding the basis of many genetic diseases. We
developed a simple new diagnostic test for Stickler syndrome that allows early detection and the ability to
medically intervene and prevent the onset of the major clinical consequences. Other studies on collagen VI in
muscular dystrophy defined new disease mechanisms, providing a new perspective on the causes of these severe
muscle disorders and allowing the development of new prenatal diagnostic methods.

Expected future outcomes:

Improved diagnostic approaches to cartilage and muscle disease Improved genetic counseling to patients
Increased understanding of disease processes and development of new therapeutic strategies

Name of contact:      John Bateman
Email of contact:     john.bateman@mcri.edu.au
                            NHMRC Research Achievements - SUMMARY


Grant ID:      156730                                            Start Year:      2000
CIA Name:      A/Pr Matthew T Gillespie                          End Year:        2004
Main RFCD:     Gene Expression                                   Total funding:   $340,000.00
Admin Inst:    University of Melbourne                           Grant Type:      NHMRC Research Fellowship


Title of research award: Senior Research Fellowship

Lay Description (from application):

No available Lay Description

Research achievements (from final report):

Research was focussed in three areas, each of which specifically focussed on the skeleton and how its structure
may be compromised. 1. In cancers that have the propensity to grow in bone, we have identified the mechanisms
by which cancers, commonly of the breast, can induce bone destruction. This provides the opportunity to target
factors expressed by cancer cells that promote the formation and activation of the bone-resorbing cells
(osteoclasts). We are now investigating agents to block the activity of these factors and determining their action in
cancer models of bone loss. 2. Arthritis. We have identified that T cells are the principle mediators to establish
bone loss that is associated with arthritis. We have for the first time provided proof in concept that bone loss can
be reduced in rheumatoid arthritis by targeting the bone resorption process. This provides a mechanism by which
the debilitating reduced joint movement may be circumvented in arthritis. 3. Immune cell function and bone. We
have provided substantial information about the impact that cells of the immune system, particularly T cells can
have both positive and negative effects upon skeleton. Whereby T cells can make products that can protect against
bone loss, enhance bone loss, or build new bone. Furthermore, we have determined that in mice deficient in one or
more of these factors, the quality of normal bone is affected. This information is useful for the management of
patients with immune deficiencies, since it highlights the potential involvement of the skeleton in conditions
where key interleukins are absent or abnormally expressed.

Expected future outcomes:

Specific therapies that reduce bone destruction will be examined in pre-clinical models and in patients to
determine whether they successfully reduce bone loss in arthiritis, cancer and auto-immune disease.

Name of contact:      Matthew Gillespie
Email of contact:     mgillespie@svi.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      209014                                             Start Year:      2002
CIA Name:      Prof Ego Seeman                                    End Year:        2004
Main RFCD:     Endocrinology                                      Total funding:   $316,320.00
Admin Inst:    University of Melbourne                            Grant Type:      Standard Project Grant


Title of research award: Is periosteal bone formation responsible for sexual dimorphism in bone fragility?

Lay Description (from application):

Men and women sustain fractures as they age because their bones become fragile. Women sustain fractures more
often than men. Bone thinning occurs in both sexes but it is usually believed that this thinning or loss of bone is
greater in women than men. We have evidence to suggest that this may not be correct. In fact, it is likely that men
and women lose a similar amount of bone, about half what they started with, but during ageing, men lay down
more bone on the outside surface of the bone than women compensating for the similar amount lost on the inside
of the bone. We also have evidence to suggest than men and women who get spine fractures do so because the
process of laying down bone may fail to occur normally. We will study these processes of bone loss inside the
bone and bone gain outside the bone to try to better understand why bones become weak. We will measure the
bone size and its density in healthy men and women and patients with fractures to determine how the increasing
size of the bone produced by laying down bone on its outside helps to keep it strong and to preserve the bone that
would otherwise be lost if it didn't occur or if a disease developed that might reduce the compensatory

Research achievements (from final report):

We studied 1013 healthy subjects (327 men, 686 women), 125 patients with spine fractures (36 men and 89
women), and 307 patients with hip fractures (127 men, 180 women). We made the following observations: At the
spine (i) reduced bone fromation on the outer surfaces (periosteum) of the verebral body during growth or
agening, may be in part responsible of verebral fragility and spinal fractures. (ii) The biomechanical index -
fracture risk indes (FRI) - is not a better predictor of spinal fractures than bone density. In addition, we found that
women, not men, with vertebral fractures may come from a population with short stature. The difference between
arm span and standing or sitting height cannot be sued to predict vertebral fracture risk. At the hip, we reported
that, differences in the geomentry between men and women were confined to further displacement of the cortex
(the wall of the bone) from neutral axis in young men compared to young women explaining why men bones are
stronger. Ageing amp;ified these differences shifting the cortex even further from the neutral axis and maintaining
the bending strength of the bone in men, but not in women. This at least partly explained the lower fracture rate in
men compared to women. Also, we observed that compared to their peers women and men with hip have reduced
cortical thickness. Women who fracture have larger bones. Where as men who fracture have smaller bones.

Expected future outcomes:

target the periosteum as a very effective way of maintaining bone strength and reducing the burden of fracture. It
is likely that bone size, independently of bone density, could be used in the future to predict fracture. We plan to
test this hypothesis emanating from this grant.

Name of contact:       Ego Seeman
Email of contact:      egos@unimelb.edu.au
                             NHMRC Research Achievements - SUMMARY
Grant ID:      145619                                           Start Year:     2001
CIA Name: A/Pr Amanda J Fosang                                  End Year:       2005
Main RFCD: Rheumatology and Arthritis                           Total funding: $685,000.00
Admin Inst: University of Melbourne                             Grant Type: Research Fellowship
Title of research award: Cartilage destruction in arthritis: Mechanism of aggrecanase and matrix
metalloproteinase action in vivo and in vitro

Lay Description (from application):
Arthritis is a disease that causes pain, deformity and disability. The lack of adequate therapies for arthritis is partly
a reflection of our limited understanding of the biochemical events involved in disease progression and cartilage
destruction. Two distinct families of enzymes are present in cartilage. These are the MMP and the ADAMTS
family. These enzyme families are important for cartilage turnover in normal growth and skeletal development.
However unregulated enzyme activity resulting in accelerated cartilage breakdown leads to the pathology
recognised as arthritis. While some activities of the MMP and ADAMTS families have been studied in the
laboratory, there have been no in vivo studies to determine which family is responsible for cartilage destruction,
and which is therefore most appropriate for targeting by drugs. This project will create genetically-modified mice,
resistant to either the MMP or the ADAMTS enzymes. The mice will be used in experimental arthritis models to
determine which enzymes play the major role in initiating disease, which enzymes are involved in disease
progression and which enzymes may be important for repair. In parallel studies, the highly specialised matrix
molecule, keratan sulphate, will be studied for its role in cartilage destruction. There is preliminary evidence to
suggest that keratan sulphate may be involved in the regulation of ADAMTS activity. The possible direct and
indirect modalities of keratan sulphate action will be investigated. The results of this arthritis project will (a) yield
new information on the mechanism of disease action; (b) identify targets for the rational design of disease-
modifying drugs; (c) elucidate biochemical processes involved in normal skeletal growth and cartilage repair; and
(d) provide new in vivo models for testing the efficacy of arthritis therapies.

Research achievements (from final report):

The ability of cartilage to protect the surface of bones from wear and tear is dependent upon the integrity of a
proteoglycan called aggrecan. In the early stages of arthritis, aggrecan is degraded by metalloenzymes and lost
from cartilage. Our laboratory is researching which families of enzymes are important in aggrecan degradation.We
have engineered two strains of genetically-modified mice: one in which the aggrecan is resistant to degradation by
matrix metalloproteinases and one in which aggrecan is resistant to degradation by aggrecanases at a key site. Our
main aim is to challenge these mice with experimental arthritis, to see whether the genetic modifications confer
protection against the onset and progression of arthritis. However, before we could do this work we needed to
make a careful analysis of the growth and development of unchallenged mice. We predicted that these mice would
have some problems with bone growth, because aggrecan remodelling is part of normal development. We were
surprised to find that both strains of mice showed no abnormalities in skeletal growth. These results indicated that
the transition from cartilage to bone that occurs during bone growth does not involve either of these families of
enzymes. Our results lead us to challenge the prevailing dogma about the mechanism of skeletal growth. Our work
also has implications for the design of arthritis therapies aimed at modulating cartilage metabolism, particularly
the use of such therapies in children and women of child bearing age. Aggrecanase-resistant mice that were
challenged with acute inflammatory arthritis proved to be less susceptible to the early loss of aggrecan from the
tissue, suggesting that preventing aggrecanase action might protect against the onset of disease (manuscript in
preparation).

Expected future outcomes:
We will investigate our new hypothesis that aggrecan remodelling during normal skeletal development is via a
non-metalloenzyme-mediated mechanism. The potential outcome from investigating this hypothesis is a new
paradigm for matrix remodelling in skeletal development From 145619 and its sister project 350487 (CIA
Fosang), we have identified aggrecanase-2 as a potential target for drug design.

Name of contact:       A/Prof. Amanda Fosang
Email of contact:      amanda.fosang@mcri.edu.au
                           NHMRC Research Achievements - SUMMARY

Grant ID:      145813                                           Start Year:      2001
CIA Name:      Prof John Hamilton                               End Year:        2005
Main RFCD:     Protein Targeting and Signal Transduction        Total funding:   $457,250.00
Admin Inst:    University of Melbourne                          Grant Type:      Research Fellowship


Title of research award: Control of monocyte/macrophage function by CSF-1

Lay Description (from application):

The project aims to understand how a factor responsible for the production of a type of white blood cell interacts
with its receptor. If we knew the molecular details of how this factor works then we would be able to control
better diseases, such as osteoporosis and arthritis, where such cells can play havoc by destroying tissue. The
project also has implications for certain leukaemias which lose growth control mechanisms in response to this
factor.

Research achievements (from final report):

I have developed a new cell system to study the influence of cytoplasmic residues of the CSF-1 receptor on the
degree of macrophage differentiation observed in response to CSF-1 and to develop proteomic technologies
including new technologies to enrich for and detect CSF-1R binding partners. By this approach we were able to
identify a new form of myosinXVIIIA243. More recent molecular studies have focussed on a proposed role for
CSF-1-induced changes in cell metabolism and survival as well as the role of integrins and the podosome in CSF-
1-induced survival and migration, respectively. The project has helped to define at a molecular level how a
particular protein controls the development of a type of white blood cell which is involved in host defence and
inflammation. Blockade of this control by antibodies has been shown in animal models to lead to less
inflammatory disease. By understanding the relevant molecular events governing the function of this molecule it is
possible that orally active drugs could be developed to achieve the same outcome.

Expected future outcomes:

Drugs will be developed to control the number and activation state of a white blood cell important for the
inflammation and tissue destruction observed in a disease such as rheumatoid arthritis. Recent evidence also
suggests that progression of certain tumours may also be slowed down in the same way.

Name of contact:      Professor John Hamilton
Email of contact:     jahami@unimelb.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      145828                                             Start Year:       2001
CIA Name:      A/Pr Thomas M Cocks                                End Year:         2005
Main RFCD:     Basic Pharmacology                                 Total funding:    $461,563.44
Admin Inst:    University of Melbourne                            Grant Type:       Research Fellowship


Title of research award: Characterisation of PAR2 knockout and transgenic mice: towards gene therapy for
epithelia based inflammatory diseases

Lay Description (from application):

Debilitating and sometimes fatal diseases like asthma and rheumatoid arthritis urgently require new approaches
for their effective management and hopefully, cure. We have recently discovered that the airways posses a
powerful and naturally-occuring protective mechanism which is regulated by unique molecules in the membranes
of the lining cells of the air passages. These molecules are called protease-activated receptors, or PARs, and are
also found on cells lining the inner surfaces of blood vessels and joints as well as in skin. We are fortunate to have
strains of mice - a species in which the PAR-mediated protective mechanism is well developed - in which the gene
for the most important of the PARs found in the lung, PAR2, is missing. These animals are called PAR2 'knock-
outs'. We also have another strain of mouse in which the human PAR2 gene has been inserted back into PAR2
knock-out mice. These animals will allow us to determine the importance of PAR2 in protection against asthma,
arthritis, vascular disease and deficiencies in skin healing, as well as how PAR2 might be a more effective
protective agent in mice rather than humans. Thus, modification of the human gene to make the protective system
work as effectively as in the mouse might provide an effective therapy or cure for diseases of the lungs, joints and
skin as well as in vascular diseases.

Research achievements (from final report):

Under my leadership over the last seven years, my group has contributed substantially to a frontier field of
medical science - protease-activated receptors (PARs) and their role in inflammation. I intend to keep my
laboratory in the forefront of this field by capitalising on discoveries that PARs play central roles in anxiety,
epileptogenesis and immunological defence against allergens and autoimmune diseases.

Expected future outcomes:

My philosophy is to maintain a balance of fundamental and applied research. Research areas to date include (1)
respiratory diseases, (2) allergy and autoimmune disease and (3) central nervous system. Each of these has
significant importance globally.

Name of contact:       Tom Cocks
Email of contact:      thomasmc@unimelb.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      170206                                             Start Year:       2001
CIA Name:      A/Pr Thomas M Cocks                                End Year:         2005
Main RFCD:     Basic Pharmacology                                 Total funding:    $575,000.00
Admin Inst:    University of Melbourne                            Grant Type:       NHMRC Research Fellowship


Title of research award: PRF Fellowship Award

Lay Description (from application):

No available Lay Description

Research achievements (from final report):

Under my leadership over the last seven years, my group has contributed substantially to a frontier field of
medical science - protease-activated receptors (PARs) and their role in inflammation. I intend to keep my
laboratory in the forefront of this field by capitalising on discoveries that PARs play central roles in anxiety,
epileptogenesis and immunological defence against allergens and autoimmune diseases.

Expected future outcomes:

My philosophy is to maintain a balance of fundamental and applied research. Research areas to date include (1)
respiratory diseases, (2) allergy and autoimmune disease and (3) central nervous system. Each of these has
significant importance globally.

Name of contact:       Tom Cocks
Email of contact:      thomasmc@unimelb.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      170207                                            Start Year:      2001
CIA Name:      A/Pr Amanda J Fosang                              End Year:        2005
Main RFCD:     Rheumatology and Arthritis                        Total funding:   $475,000.00
Admin Inst:    University of Melbourne                           Grant Type:      NHMRC Research Fellowship


Title of research award: Senior Research Fellow, Level A appointment

Lay Description (from application):

No available Lay Description

Research achievements (from final report):

The ability of cartilage to protect the surface of bones from wear and tear is dependent upon the integrity of a
proteoglycan called aggrecan. In the early stages of arthritis, aggrecan is degraded by metalloenzymes and lost
from cartilage. Two members of the ADAMTS metalloenzyme family, ADAMTS-4 and ADAMTS-5 are
particularly active against aggrecan in vitro, but the extent to which each acts in vivo was previously unknown.
We engineered two strains of mice lacking functional ADAMTS-4 or ADAMTS-5 and showed that deleting
ADAMTS-5 alone is sufficient to halt the progression of inflammatory arthritis in the mouse. This finding was
published back-to-back in Nature with another report from Wyeth, USA, showing that ADAMTS-5 is also the
primary aggrecanase in a mouse model of osteoarthritis. These studies generated much excitement in the field,
highlighting ADAMTS-5 as an important new target for the development of arthritis therapies. We developed a
further two strains of mice in which we mutated the aggrecan substrate. In one strain, aggrecan was made resistant
to degradation by matrix metalloproteinases and in the other, aggrecan was made resistant to degradation by
aggrecanases. We predicted that these modifications would confer protection against the onset and progression of
arthritis, and indeed this proved to be true for the aggrecanase-resistant mice, in an inflammatory model of
arthritis. Most unexpected, however, was our discovery that the transition from cartilage to bone that occurs
during normal bone growth does not involve either matrix metalloproteinases or aggrecanases. These results lead
us to challenge the prevailing dogma about the mechanism of skeletal growth. Our work also has implications for
the design of arthritis therapies aimed at modulating cartilage metabolism, particularly the use of such therapies in
children and women of child bearing age.

Expected future outcomes:

We will investigate our new hypothesis that aggrecan remodelling during normal skeletal development is via a
non-metalloenzyme-mediated mechanism. The potential outcome from investigating this hypothesis is a new
paradigm for matrix remodelling in skeletal development From 170207 and its sister project 350487 (CIA
Fosang), we have ADAMTS-5 as a potential target for drug design.

Name of contact:       A/Prof. Amanda Fosang
Email of contact:      amanda.fosang@mcri.edu.au
                           NHMRC Research Achievements - SUMMARY

Grant ID:     170208                                           Start Year:      2001
CIA Name:     Prof John Hamilton                               End Year:        2005
Main RFCD:    Rheumatology and Arthritis                       Total funding:   $457,250.00
Admin Inst:   University of Melbourne                          Grant Type:      NHMRC Research Fellowship


Title of research award: Control of monocyte/macrophage function by CSF-1

Lay Description (from application):

No available Lay Description

Research achievements (from final report):

I have developed a new cell system to study the influence of cytoplasmic residues of the CSF-1 receptor on the
degree of macrophage differentiation observed in response to CSF-1 and to develop proteomic technologies
including new technologies to enrich for and detect CSF-1R binding partners. By this approach we were able to
identify a new form of myosinXVIIIA243. More recent molecular studies have focussed on a proposed role for
CSF-1-induced changes in cell metabolism and survival as well as the role of integrins and the podosome in CSF-
1-induced survival and migration, respectively. The project has helped to define at a molecular level how a
particular protein controls the development of a type of white blood cell which is involved in host defence and
inflammation. Blockade of this control by antibodies has been shown in animal models to lead to less
inflammatory disease. By understanding the relevant molecular events governing the function of this molecule it is
possible that orally active drugs could be developed to achieve the same outcome.

Expected future outcomes:

Drugs will be developed to control the number and activation state of a white blood cell important for the
inflammation and tissue destruction observed in a disease such as rheumatoid arthritis. Recent evidence also
suggests that progression of certain tumours may also be slowed down in the same way.

Name of contact:      Professor John Hamilton
Email of contact:     jahami@unimelb.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      247909                                            Start Year:      2003
CIA Name:      Dr Evange Romas                                   End Year:        2005
Main RFCD:     Rheumatology and Arthritis                        Total funding:   $435,000.00
Admin Inst:    University of Melbourne                           Grant Type:      New Investigator


Title of research award: Modulation of osteoclast formation and function to prevent joint destruction in
rheumatoid arthritis

Lay Description (from application):

Rheumatoid arthritis is a disease that affects about 200,000 Australians. It is characterised by painful joint
destruction leading to work disability, diminished quality of life and decreased life expectancy. The usual
treatment of arthritis leads to less inflammation however it cannot be relied upon to control bone and joint
destruction. Patients often have long term worsening of joint function despite short and medium term
improvement in joint pain and swelling. One reason for this paradox may be that while research has mainly
focused on inflammation, far less is known about the processes responsible for bone damage. Normally,
specialised bone cells called "osteoclasts" carry out bone breakdown during growth and maintenance of the
skeleton. In rheumatoid arthritis, these cells are responsible for the joint damage; this proposal, therefore, focuses
on inhibiting the activity of these cells as a new therapy. So far, our work using a model of human rheumatoid
arthritis has demonstrated that it is possible to separate joint inflammation from joint damage by selectively
targeting osteoclasts with an inhibitor known as "Osteoprotegerin". Besides Osteoprotegerin, we have identified
two novel molecules named OCIL and sFRP-1 and shown that they are present in the joints of animals and
humans with arthritis. Very recent experiments in our laboratory show that in the test tube, OCIL and sFRP-1 (like
Osteoprotegerin) block osteoclast activity. The sFRP-1 molecule may also block a very important messenger
molecule in arthritis called tumour necrosis factor. We therefore propose to study the effect of OCIL and sFRP-1
in the joints of mice with arthritis. We expect that these new inhibitors will have favorable effects on joint
damage. If so, they could undergo further testing for use in humans. We believe that investigations along these
lines may provide a rationale for an entirely new treatment approach to improve the long term outcome for
patients with arthritis.

Research achievements (from final report):

Joint damage in rheumatoid arthritis causes pain, disability and loss of function. The research team employed
animal models of rheumatoid arthritis to elucidate the mechanism of arthritic damage. A major discovery was that
the mechanism of bone destruction in arthritis is entirely different to the mechanism of cartilage injury. It was
determined that the cells responsible for bone damage were osteoclasts. The osteoclasts are generated in the joints
by the action of locally produced inflammatory molecules especially TNF-alpha and RANKL, and when present
in large numbers, these cells remove excessive amounts of bone and degrade joint structure. This process can lead
to joint deformity, pain and loss of function. It was shown that reducing the numbers and or activity of osteoclasts
with drugs such as Osteoprotegerin (OPG) or Zoledronic acid could effectively reduce bone erosion and damage
in models of arthritis. These discoveries suggest that regulating the number of osteoclasts in the skeleton could
effectively minimise or even prevent joint destruction in rheumatoid arthritis.

Expected future outcomes:

Treatment for rheumatoid arthritis is often unsatisfactory because joint damage may continue even when
inflammation is controlled. The identification of specific pathways that lead to bone erosion allows for reliable
prevention of joint damage and deformity. New strategies that target osteoclasts, TNF or RANKL are likely to
become important facets of therapy for arthritis.

Name of contact:       Dr. E. Romas
Email of contact:      evange.romas@svhm.org.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      247930                                            Start Year:      2003
CIA Name:      Dr Natalie A Sims                                 End Year:        2005
Main RFCD:     Endocrinology                                     Total funding:   $0.00
Admin Inst:    University of Melbourne                           Grant Type:      Biomedical CDA


Title of research award: Career Development Award

Lay Description (from application):

No available Lay Description

Research achievements (from final report):

In the time of this Career Development Award, Dr Sims identified a number of new gene products that regulate
bone formation, bone growth and bone destruction. The new gene products, and others that interact with them are
of potential benefit as therapeutic agents for osteoporosis, arthritis, dwarfism and other diseases of the skeletal
system. Her work has also focussed on understanding the only known "bone-building" agent currently approved
for human therapy, parathyroid hormone (PTH). Her work has determined which local gene products are regulated
by PTH, to further understand the mechanism of action of this therapeutic agent. She also established models of
arthritis and successfully used inhibitors of bone destruction to prevent bone destruction associated with
inflammatory arthritis. Her progress on this work was so significant that she was awarded an NHMRC Research
Fellowship 2 years before the completion of the Career Development Award.

Expected future outcomes:

Her work continues to identify novel genes that regulate the activity of bone cells, and particularly those genes
involved in communication between the cells of bone stimulated by PTH. These too, may provide useful drug
targets and improve our understanding of the way the skeleton, and the cells within it, work.

Name of contact:      Natalie Sims
Email of contact:     nsims@svi.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      251638                                            Start Year:      2003
CIA Name:      A/Pr Mark A Kotowicz                              End Year:        2005
Main RFCD:     Endocrinology                                     Total funding:   $410,500.00
Admin Inst:    University of Melbourne                           Grant Type:      Standard Project Grant


Title of research award: Bone size and bone turnover: relationship to fracture risk over ten years

Lay Description (from application):

The occurrence of fracture in the ageing population is a major public health problem because these fractures are
responsible for considerable morbidity and mortality. Of women reaching 90 years of age, one third will fracture
their hip and overall, one in every six women will sustain an osteoporotic fracture in her lifetime. The direct cost
to the community is unknown but estimated, conservatively, at 175 million dollars annually. Most of this is likely
to be the result of hip fractures which occupy an estimated 400,000 bed-days annually. This bed occupancy is
fourth next to mental illness, cardiac disease and cancer. The Geelong Osteoporosis Study is a large population-
based epidemiological study currently under way to evaluate the major risk factors for fracture in women . This
present study which will be an extension of the study to date, will provide in total, 8-10 years of data concerning
the processes that result in increased bone fragility and fracture.

Research achievements (from final report):

The present study is an extension of the Geelong Osteoporosis Study, a large population-based epidemiological
study designed to evaluate major fracture risk factors in women, and provides up to 10 years of data about the
development of bone fragility and fracture. We have shown that hip fracture patients have thinning of the outer
shell of the thigh bone that likely compromises bone strength and that there is a compensatory increase in the
diameter of the bone. Additional information about the biomechanical implications of these structural changes will
become available when Hip Structure Analysis of all bone densitometry scans is complete. We have developed a
clinically useful fracture risk (FRISK) score that predicts fracture by combining information from bone
densitometry, previous fracture and falls history. The FRISK score predicts 75% of fractures over a 2 year period.
Systemic inflammation, as assessed by measurement of high sensitive C-reactive protein (hsCRP), predicts
fracture risk over and above information provided by bone densitometry. The role of vitamin D, the influence of
drug exposures, the nervous system, genetic factors, oxidative stress and depression in bone fragility have been
reported. We have demonstrated that the population burden of fracture comes from the large number of
individuals with a modest reduction in bone mass rather than the relatively small number of high-risk individuals
with osteoporosis. Reference ranges for bone densitometry have been established, the health impact of fragility
fracture and cost benefit analyses of treating women with osteopenia and osteoporosis have been published.

Expected future outcomes:

Development of an updated FRISK score incorporating bone turnover markers and hsCRP, pursuit of a common
aetiology for osteoporosis and cardiovascular (CVD) disease based on predictive value of hsCRP in both disorders
and evidence of systemic inflammation in CVD, evaluation of osteoporosis in men using expertise gain from this
study (NHMRC Project 299831)

Name of contact:      Assoc Prof Mark Kotowicz
Email of contact:     markk@BarwonHealth.org.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      209168                                          Start Year:      2002
CIA Name:      Dr Kay M Crossley                               End Year:        2006
Main RFCD:     Rehabilitation and Therapy: Occupational and Physical            Total funding: $138,527
Admin Inst:    University of Melbourne                         Grant Type: Health Professional Research
                                                               Fellowship
Title of research award: Factors affecting motor control and loading of the patellofemoral joint

Lay Description (from application):

No available Lay Description

Research achievements (from final report):

Joint swelling and pain are hallmarks of many knee conditions, particularly knee osteoarthritis in adults and the
elderly and patellofemoral pain in adolescents or adults. Such conditions are also frequently associated with
altered thigh muscle function, including weakness, inhibition and altered activation, which occur in the absence of
damage to the muscle itself. It is not known whethe the pain or swelling directly influences this thigh muscle
function. This research was a series of studies, primarily conducted in healthy people. These studies involved the
injection of pain provoking substance into the knee and evaluating the effects of the resulting knee pain on thigh
muscle function. The results of this study demonstrated that the induced knee pain resulted in alterations in the
amount and timing of thigh muscle activity, and the way that people walk. The other study involved injecting fluid
into the knee to mimic knee swelling. Similar to the knee pain study, this artificial swelling resulted in alterations
in the amount and timing of thigh muscle activity in the during functional tasks. The results of these study provide
compelling evidence that knee pain and swelling have considerable effects on thigh muscle function and must be
addressed in order to attain successful rehabilitation of painful knee conditions


Name of contact:       Kay Crossley
Email of contact:      k.crossley@unimelb.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:       299831                                              Start Year:     2004
CIA Name: Prof Geoffrey Nicholson                                   End Year:       2006
Main RFCD: Endocrinology                                            Total funding: $424,883.00
Admin Inst: University of Melbourne                                 Grant Type: Standard Project Grant
Title of research award: Male osteoporosis: a population-based study in Geelong
Lay Description (from application):
Osteoporosis is a term used to indicate that bones have become thin and fragile. During the ageing process bone
fragility increases and fractures occur more easily and more often. Fractures may also occur during normal daily
activities, with fractures of the spine, forearm and hip being common. However, many other sites may fracture.
This is a serious problem because fractures cause pain, disability and, sometimes, death. Although previously
overshadowed by its effect in women, osteoporosis is increasingly being recognised in men. In Australia, 39% of
all fractures occur in men and prognosis for fracture in men is worse than in women. A consequence of increasing
male longevity is that osteoporosis will affect a growing number of Australian men. It is anticipated that between
1996 and 2051, the number of men with fracture will double, with a 4-fold increase in the number of male hip
fractures. Unless the problem of osteoporosis in men is addressed and effective interventions are implemented, the
substantial health burden imposed by age-related fractures will continue to escalate. In this case-control study of
fracture risk in men, men with fractures (cases) will be identified prospectively for 3 years from radiological
reports. Controls will be selected concurrently, at random from electoral rolls. Anticipated number of cases and
controls are 800 and 1400, respectively. Cases and controls will be characterised for risk factors for fracture: bone
density and bone geometry will be measured, serum samples collected, and diet, lifestyle and medical history
documented by questionnaire. The advantage of this type of data is that information from patients with fracture
will be used to tell us about the risk of fracture in healthy, unaffected men and about the characteristics of the
Australian male population at risk for fracture. The information can be used in decision making for the individual
and in policy making for the whole population.

Research achievements (from final report):

This large population-based epidemiological study enrolled 1,540 men (aged 20-97 years) to evaluate major
fracture risk factors. Assessments included bone mineral density (BMD), demographic, anthropometric and
clinical data; diet; osteoporosis risk factors; medical, falls and fracture history; drug exposures; muscle strength
and gait; and fasting blood samples for biochemical, hormonal and genetic analysis. BMD reference ranges will be
made available for use on all densitometers across Australia, once finalised. Using bone densitometry,
measurement of vertebral height identified alterations in vertebral dimensions that define fracture. We have
determined age distribution of newly recognised vertebral fractures for ambulatory men and shown that these
fractures remain largely undiagnosed, are associated with poor quality of life, compromised mobility, balance and
physical activity. Relatively few high trauma fractures occur among elderly men whereas they predominate in
younger men. Among men with depression, BMD is reduced, suggesting that depression may be an osteoporosis
risk factor. Metabolic syndrome, a combination of features realted to obesity associated with increased risk
cardiovascular was identified in nearly 1/3 of middle-aged and elderly men. These men have increased BMD,
possibly related to skeletal loading. We have also reported that men with prostate cancer have reduced BMD.
Magnetic resonance imaging was explored as a promising technique for identifying structural parameters of bone
associated with ageing and bone fragility.

Expected future outcomes:

Development of a clinically useful fracture risk score incorporating multi-site bone mineral density, clinical risk
factors, biomarkers and structural parameters of bone, investigation of a common aetiology for osteoporosis and
depression based on predictive value of markers of inflammation and inflammatory cytokines, further evaluation
of the metabolic syndrome in men.

Name of contact:       Assoc Prof Julie Pasco
Email of contact:      juliep@barwonhealth.org.au
                           NHMRC Research Achievements - SUMMARY

Grant ID:      299944                                         Start Year:     2004
CIA Name: Dr Andrew D Cook                                    End Year:       2006
Main RFCD: Rheumatology and Arthritis                         Total funding: $473,250.00
Admin Inst: University of Melbourne                           Grant Type: Standard Project Grant
Title of research award: The role of the plasminogen activators (PA), urokinase PA and tissue-type PA, in
arthritis

Lay Description (from application):
Many diseases, such as rheumatoid arthritis (RA), are inflammatory by nature. Intra-articular fibrin deposition is
an early and persistent hallmark of inflammatory responses, resulting from an altered balance between coagulation
(the production of fibrin) and fibrinolysis (the breakdown of fibrin). This fibrin accumulation can have adverse
effects in RA, including mediating and/or enhancing inflammation, and contributing to subsequent joint damage.
The plasminogen activators (PA), urokinase PA (u-PA) and tissue-type PA (t-PA) convert plasminogen into
plasmin which can then breakdown the accumulated fibrin. Their presence in RA patients would therefore be
beneficial. However, u-PA is also implicated in cell migration leading to inflammatory cells accumulating in the
joint, and cartilage destruction, both of which are detrimental to disease outcome. In the joints of RA patients
there are high levels of u-PA and low levels of t-PA. We, and our collaborators, have found that in the absence of
t-PA, disease is exacerbated, whilst in the absence of u-PA, the outcome depends on the type of disease, either
exacerbating or ameliorating disease. This highlights the different roles u-PA can have. The current proposal aims
to determine the role of u-PA in inflammation and arthritis, and whether enhancing t-PA can have beneficial
outcomes with respect to disease severity. In addition, we will also study whether intra-articular fibrin deposition
can, in fact, drive the inflammatory reaction and cartilage destruction seen in RA. The findings will be important
for our understanding of the role of fibrin accumulation in the inflammatory and destructive processes that occur
in RA, and the roles of u-PA and t-PA in enhancing and preventing them respectively. Information gained will
provide clues for useful strategies for the treatment of human inflammatory diseases, including RA.

Research achievements (from final report):

Many diseases, such as rheumatoid arthritis (RA), are inflammatory by nature. Fibrin deposition within the joint is
an early and persistant hallmark of inflammatory responses, resulting from an altered balance between coagulation
(the production of fibrin to form a clot) and fibrinolysis (the breakdown of fibrin). This fibrin accumulation can
have adverse effects in RA, including mediating and/or enhancing inflammation, and contributing to subsequent
joint damage. The plasminogen activators (PA), tissue-type PA (t-PA) and urokinase PA (u-PA), convert
plasminogen to plasmin which can breakdown fibrin. The presence these PAs in RA would therefore be
beneficial. However, u-PA is also implicated in cell migration leading to inflammatory cells accumulating in the
joint, and cartilage destruction, both of which are detrimental to disease outcome. We have found that t-PA and u-
PA do indeed have differing roles during inflammatory responses and arthritis development, with the main action
of t-PA being in fibrin breakdown, whereas u-PA has several roles and its main action differs depending on the
type of inflammatory response. u-PA appears to play a role in ther activation of the complement system which
forms part of our immune system destroying pathogens, and which is implicated in RA. Chronic inflammatory
diseases, such as RA, are a vast burden to the community and represent unmet medical needs. The benefits of
understanding the differing roles of the PAs in inflammation and disease means more specific therapies can be
developed. A therapy that targets u-PA, but not t-PA, is likely to be beneficial for the treatment of RA.

Expected future outcomes:

Future outcomes will include a better understanding of the role urokinase plasminogen activator (u-PA) plays in
complement activation, which will have implications not only for rheumatoid arthritis (RA), but many other
diseases. More targetted treatments specific for u-PA or tissue-type PA are also likely given our better
understanding of their differing roles in inflammation and disease.

Name of contact:      Andrew Cook
Email of contact:     adcook@unimelb.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      299968                                            Start Year:       2004
CIA Name:      Prof John D Wark                                  End Year:         2006
Main RFCD:     Endocrinology                                     Total funding:    $0.00
Admin Inst:    University of Melbourne                           Grant Type:       Standard Project Grant


Title of research award: Smoking cessation and bone health: observational and intervention studies in twins and
a Quitline population

Lay Description (from application):

Osteoporosis is a major health problem that causes bones to break (fracture) easily. Many bones are susceptible,
with hip fractures being the worst outcome of osteoporosis. They cause pain, disability, require major health
interventions (surgery and rehabilitation), lead to death in about 20% of cases, and the overall care of hip fracture
patients is very expensive. Osteoporosis is treated to reduce the risk of fractures. The prevention and treatment of
osteoporosis should include avoidance of factors known to bring on or worsen the condition. Smokers are known
to have an increased risk of osteoporosis and fractures. However, it is not known how smoking brings on
osteoporosis. Importantly, neither is it clear whether quitting smoking leads to improved bone health (and a
reduced risk of fractures). These are important questions for the community in general and for smokers with
osteoporosis in particular. We will endeavour to answer these questions by studying twins who do and do not
smoke and by observing what happens to measures of bone health (bone mineral density and other factors) in
people attempting to quit smoking. New information gained from these studies may lead to better ways of
avoiding or treating the damage that smoking does to bone. We may also become able to predict the benefit to
bone when people quit smoking.

Research achievements (from final report):

Study 1: we have recruited and evaluated 84 smoking-discordant twin pairs. This approaches the conservatively
estimated required sample of 86 pairs. 34 of these pairs were seen at the RMH site, 50 at RNSH. Study 2:
recruitment of smoking-concordant twin pairs, both willing to cease smoking, has proven difficult. To date, 7 pairs
have been recruited and completed visits at the RMH site, 1 twin pair at RNSH; conservatively, 28 pairs were
required and recruitment is ongoing. We have also completed a controlled, short-term smoking cessation trial in
48 subjects (32 smokers, 16 non-smokers) to augment the data to be obtained in the smoking-concordant twin
smoking cessation study. Samples are ready for analysis in this study. Study 3: a long-term smoking cessation
study in Quitline callers; we have recruited 419 subjects to date. This is at our recruitment target, which appears
very conservative given a very high retention rate in this group. The quitting rate at 2 weeks is 63%, at 6 months
37% and at 12 months 33%. These figures are a little greater than reported in the literature and are re-assuring
regarding the adequacy of our sample size. To date, 113 subjects have completed 1 year visits.

Expected future outcomes:

(i) to improve understanding of the mechanisms underlying the bone deficits and increased fracture risk observed
in smokers compared with non-smokers, (ii) to examine the reversibility of smoking-associated bone and mineral
abnormalities.

Name of contact:       Professor John D Wark
Email of contact:      jdwark@unimelb.edu.eu
                            NHMRC Research Achievements - SUMMARY

Grant ID:       251682                                             Start Year:      2003
CIA Name: Prof Geoffrey Nicholson                                  End Year:        2007
Main RFCD: Primary Health Care                                     Total funding: $293,000.00
Admin Inst: University of Melbourne                                Grant Type: Standard Project Grant
Title of research award: Primary Care Prevention of falls and fractures in the elderly by vitamin D
supplementation.
Lay Description (from application):
While Australia has one of the highest rates of skin cancer, many of us are not receiving enough sun exposure to
adequately maintain necessary blood levels of vitamin D. For years it was assumed that vitamin D deficiency was
rarely seen in Australia where sunlight abounds for most of the year. Although few foods are high in vitamin D, it
was thought that only certain cultural groups where women are always veiled in public, very dark-skinned people
and the housebound elderly, were at risk of vitamin D deficiency. Lower vitamin D levels following wintertime
have now been reported in many populations including those living near the Mediterranean and in Geelong,
Victoria. Vitamin D insufficiency is associated with an increased risk of falling through increased body sway and
muscle weakness. Low levels of the vitamin also encourage the removal of calcium from bones and will
predispose to bone fracture for two reasons - increased likelihood of falling and increased bone fragility and
osteoporosis. Osteoporotic fractures are amongst the most important causes of ill-health among elderly people,
causing an estimated 65,000 fractures in 2000-01. If nothing is done, fracture rates are estimated to increase from
one every 8.1 minutes in 2001, to one every 3.7 minutes in 2021. Falls among the elderly are also a major health
with about a third of people over 70years falling at least once every year. Almost 90% of all hip fractures result
from the impact of a fall. This project will trial an annual dose of vitamin D to the elderly at high risk of vitamin D
deficiency, falls and fractures. Fifteen hundred women will be supplemented with either vitamin D or a placebo
"dummy" pill at the beginning of winter for five years. The supplementation will take place through their local
doctor and researchers will expect to see fewer falls and bone fractures occurring in those receiving vitamin D
than in the group receiving the placebo.

Research achievements (from final report):
The Vital D study successfully recruited 2,317 women aged at least 70 years and who were assessed as at a higher
risk of fragility fracture or osteoporosis. Although the initial NHMRC 5-year grant funding has finished, the study
has been awarded further NHMRC funding to extend the project's outcomes. All participants will complete the
study during 2008. The findings have been extended to investigate not only the prevention of falls and fractures,
as originally planned but also to investigate if vitamin D supplementation improves mental health in the elderly
and if vitamin D supplementation over a number of years reduces the overall use and cost of medical and hospital
services. Since commencing this project in 2003 the many potential benefits of an adequate to high vitamin D
status has received much scientific attention. The project's pragmatic design continues to have much appeal. The
concept of a once-a-year dose of vitamin D tablets holds promise as several international studies on vitamin D
supplementation have reported low compliance of the study tablets when participants were required to take
calcium and vitamin D tablets on a daily basis. The results of these other studies generally show that vitamin D
prevents falls and fractures when targeted to participants likely to have a low vitamin D status. Not surprisingly
when the analysis of results includes both those participants who took the daily supplementation and those
participants who were asked to but didn't take the tablets on a regular basis, the evidence that vitamin D prevents
falls and fractures is weaker. The results of other studies has also shown that the dose of vitamin D needs to be
sufficiently large to increase the levels of the vitamin in the blood and to show benefits to bone health. Participants
in our study -Vital D randomised to vitamin D have been given an annual dose of 500,000 IU of vitamin D3
(cholecalciferol). This dose continues to be regarded as sufficiently high.
Expected future outcomes:

The main analysis comparing falls and fractures in participants taking the vitamin D tablets with those taking
placebo will commence later this year when all participants have finished the study and the research team are no
longer 'blinded' as to their active or placebo status.

Name of contact:       Dr Kerrie Sanders
Email of contact:      kerrie@barwonhealth.org.au
                           NHMRC Research Achievements - SUMMARY

Grant ID:        350346                                          Start Year:       2005
CIA Name: Dr Rachel A Davey                                      End Year:         2007
Main RFCD: Orthopaedics                                          Total funding: $480,750.00
Admin Inst: University of Melbourne                              Grant Type: Standard Project Grant
Title of research award: The role of androgens in osteoblast development and bone metabolism.
Lay Description (from application):
Maintenance of the skeleton involves the processes of bone formation by cells known as osteoblasts and bone
breakdown by cells known as osteoclasts. When these processes become unbalanced, bone loss results, which is
the basis of osteoporosis. The reduced bone mass found in osteoporosis leads to an increased susceptibility to bone
fracture. 1 in 2 women and 1 in 3 men over the age of 60 will suffer a fracture due to osteoporosis. The increasing
incidence of osteoporotic fractures has lead to renewed efforts to understand the actions of hormones on bone.
Androgens, the male sex hormones, have beneficial effects on skeletal growth and bone maintenance in both
males and females by stimulating osteoblasts. It is believed that androgens act by binding to a specific protein
known as the androgen receptor (AR), which is only found in androgen-responsive cells. Although it is well
documented in human and animal models that androgens stimulate osteoblasts to increase the formation of bone,
the way in which they act on osteoblasts remains poorly understood. The aim of this project is to investigate the
effects of androgens at different stages of the developing osteoblast. This will be achieved by making transgenic
mice in which the androgen receptor has been inactivated only in osteoblasts at specific stages of their
development. We hypothesise that the inactivation of the androgen receptor will have dramatic effects on the
development and function of osteoblasts.This project will help clarify the role androgens play in bone formation
and will give fundamental insights into the basic biology of bone in both normal and disease processes. As
androgens are one of the few agents that act to increase bone formation, understanding the way in which they act
is important for the treatment of osteoporosis in males and females. We believe that this research is of great
importance as osteoporosis becomes more prevalent in our aging population.

Research achievements (from final report):
The aim of this research was to investigate the role of the male sex hormones, androgens, in the development and
function of the bone forming cells (osteoblasts), in males. To achieve this we generated and characterised a
number of in vivo mouse model systems in which the target for androgens, the androgen receptor (AR), was
inactivated either a) in all tissues (Global-ARKOs) or b) specifically in osteoblasts (OBL-ARKOs). The first aim
was to determine the effect of inactivating the AR in all tissues by generating Global-ARKO mice. Global-ARKO
males had female external genitalia and decreased bone due to increased bone resorption (breakdown). These data
clearly show that the actions of androgens via the AR are indispensable for male sexual differentiation and bone
maintenance. The second aim was to determine the effect of inactivating the AR only in mature osteoblasts. This
led to vertebral bone loss due to increased bone resorption, thereby demonstrating that androgens acting directly
via the AR in mature osteoblasts to maintain bone by regulating bone resorption. The final aim of this project was
to determine the effect of inactivating the AR only in mineralising osteoblasts. This resulted in trabecular and
cortical bone loss due to increased bone resorption and abnormalities in the mineralisation of bone matrix. Our
findings demonstrate that androgens act via the AR in mineralising osteoblasts to maintain bone by regulating
bone resorption and the coupling of bone matrix synthesis to mineralization. This action is most important during
times of bone accrual and high rates of bone remodelling. These studies have further advanced our understanding
of how the male sex steroids act on bone. This knowledge will allow us to further understand how bone diseases
such as osteoporosis develop, which in turn, will provide avenues for the prevention and reversal of bone fragility
in both men and women.

Expected future outcomes:
This research is currently further investigating the mechanism of androgen action on bone by identifying target
genes that are directly regulated by the androgen receptor in osteoblasts.

Name of contact:      Dr Rachel Davey
Email of contact:     r.davey@unimelb.edu.au
                           NHMRC Research Achievements - SUMMARY
Grant ID:      350487                                           Start Year:      2005
CIA Name:      A/Pr Amanda J Fosang                             End Year:        2007
Main RFCD:     Orthopaedics                                     Total funding:   $547,000.00
Admin Inst:    University of Melbourne                          Grant Type:      Standard Project Grant


Title of research award: The role of ADAMTS-4 and ADAMTS-5 in healthy and diseased cartilage: a gene
targeting approach

Lay Description (from application):

In healthy joints the proteoglycan, aggrecan, gives cartilage compressive resilience to permit weight bearing, but
in disease aggrecan is degraded by ADAMTS enzymes. The challenges to the field are to determine which
ADAMTS is involved, when these enzymes are active and precisely where they come from. We hypothesise that
ADAMTS-4 and/or ADAMTS-5 is involved in cartilage pathology. To test this hypothesis we aim to [1] Generate
mice containing mutant ADAMTS-4 and/or -5 in all cells, or [2] in cartilage cells only. [3] Analyse mutant mice
for changes in skeletal architecture, changes in ADAMTS mRNA and protein, and changes in aggrecan
breakdown products. [4] Assess disease severity in mutant mice in in vivo models of joint disease. We already
have mice with ADAMTS-4, or -5, mutated in all tissues and we are generating the double mutants now. We will
also generate single and double mutants with dysfunctional enzymes in cartilage only. We will examine skeletal
structure by histology and X-ray at all ages and monitor for expression of ADAMTS-1 and -9 to detect any
compensatory over-production of other potential 'aggrecanases'. We will also do co-culture experiments in which
cartilage and synovial cells from combinations of mutant and control mice will be incubated together to determine
whether synovial ADAMTS can penetrate and degrade aggrecan in cartilage. Finally we will induce arthritis in
mutant and control mice and monitor them to detect differences in the time of disease onset, the rate of disease
progression and overall disease severity. A comparison of whole-mouse with cartilage only mutants in the in vivo
models will complement the in vitro co-culture studies and determine whether other joint tissues such as synovium
and joint capsule can also produce ADAMTS enzymes that destroy cartilage. This is not known. Together these
experiments will reveal if, where and when ADAMTS-4 and/or -5 are active, and whether indeed they are the best
targets for drug development.

Research achievements (from final report):

The ability of cartilage to protect the surface of bones from wear and tear is dependent upon the integrity of a
proteoglycan called aggrecan. In the early stages of arthritis, aggrecan is degraded by metalloenzymes and lost
from cartilage. Our laboratory is researching which families of enzymes are important in aggrecan degradation.
We have engineered mutant mice that lack active 'aggrecanases' and studied these mice in experimentally-induced
arthritis. We discovered that an enzyme called ADAMTS-5 is the major aggrecanase in mice; we published this
work in the world-premier journal, Nature in 2005. The attention of arthritis researchers and the pharmaceutical
industry has since focussed on ADAMTS-5, for further study and for the design of arthritis therapies.

Expected future outcomes:

ADAMTS-5 inhibitors will join the list of compounds being tested for potential as arthritis therapies.

Name of contact:      A/Prof. Amanda Fosang
Email of contact:     amanda.fosang@mcri.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      400144                                           Start Year:      2005
CIA Name:      Prof John Hamilton                               End Year:        2007
Main RFCD:     Clinical Sciences not elsewhere classified       Total funding:   $334,000.00
Admin Inst:    University of Melbourne                          Grant Type:      Development Grant


Title of research award: Development of a highly potent, fully human anti-GM-CSF monoclonal antibody

Lay Description (from application):

Many diseases, such as arthritis, have unwanted inflammatory reactions. Better drugs are needed to control
inflammation. A powerful antibody to a significant pro-inflammatory cytokine will be generated; this antibody
will be especially designed so that it will not be rejected by patients. Because of its properties it will cost the
community less than similar therapeutics. Because inflammatory diseases are common many patients will benefit
from our therapeutic.

Research achievements (from final report):

The generation of a truly human neutralizing anti-GM-CSF antibody.

Expected future outcomes:

The development of such an antibody for clinical trials.

Name of contact:      Professor John Hamilton
Email of contact:     jahami@unimelb.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      350297                                        Start Year:            2004
CIA Name:      Prof Kim L Bennell                            End Year:              2008
Main RFCD:     Rehabilitation and Therapy: Occupational and Physical                Total funding: $476,575.00
Admin Inst:    University of Melbourne                       Grant Type:            Standard Project Grant


Title of research award: Efficacy of laterally wedged insoles on symptoms and disease progression in knee
osteoarthritis.

Lay Description (from application):

Knee arthritis is a painful, disabling, costly condition particularly affecting the elderly. As there is presently no
cure for knee arthritis, strategies that slow progression of the disease will reduce the personal and societal burden
of arthritis. Most research has focussed on drug therapies, which are effective in reducing pain and disability but
have side effects and are expensive. Insoles worn inside the shoes are a simple, cheap, self-administered
intervention with the potential to slow disease progression in certain patients, in addition to managing symptoms.
However, to date there has been little quality research investigating the effectiveness of insoles in knee arthritis.
This study aims to see whether 12 months of wearing insoles can lead to improvements in knee pain and function
and slow disease progression in 200 people with knee arthritis. It will use state-of-the-art technology, magnetic
resonance imaging, to measure changes in the amount of knee cartilage. This research is timely and the findings
will be of major significance as there is increasing world-wide attention on slowing progression of knee arthritis.
Insoles are one of the few non-drug therapies with the potential to influence both symptoms and disease
progression. If the results show that insoles are beneficial, then this research will: 1. Better inform clinical
guidelines to firmly recommend insoles to manage knee arthritis 2. Provide the basis for developing education
strategies for health care practitioners and patients about the benefits of insoles 3. Provide the impetus to make
insoles more readily available directly to patients 4. Ultimately lead to better patient outcomes

Research achievements (from final report):

This study was a clinical trial that investigated the efficacy and cost effectiveness of lateral wedge shoe insoles for
the treatment of knee osteoarthritis. Two hundred people with mild to moderate knee osteoarthritis were recruited
from the community by print and radio media. Participants were randomised into a lateral wedge insole or a
placebo insole group. Both groups were asked to wear the insoles everyday in their shoes for 12 months. The
groups were assessed at baseline and at 12 months with the main outcome measure being pain and function
assessed by self report questionnaires and cartilage volume assessed by magnetic resonance imaging. A cost
effectiveness analysis will also be undertaken. This study provides information that assists in evidence based
recommendations for the management of knee osteoarthritis. Specifically it provides evidence about the role of
lateral wedge insoles for reducing pain and slowing disease progression.

Expected future outcomes:

It is anticipated that this study will be used to inform clinical guidelines relating to the management of knee
osteoarthritis. The results will be used by health practitioners to assist them to better manage their patients with
this knee condition. People with knee osteoarthritis will also be informed as the benefits or otherwise of lateral
wedge insoles.

Name of contact:       Prof Kim Bennell
Email of contact:      k.bennell@unimelb.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:       400056                                              Start Year:       2006
CIA Name: A/Pr Amanda J Fosang                                      End Year:         2008
Main RFCD: Rheumatology and Arthritis                               Total funding: $518,700.00
Admin Inst: University of Melbourne                                 Grant Type: Standard Project Grant
Title of research award: How important is collagen destruction in arthritis? A study with collagenase-resistant
mice
Lay Description (from application):
Aggecan and collagen are important structural molecules in cartilage. Together they allow cartilage to bear weight
and resist compression. In arthritis, collagen is degraded by collagenases and aggrecan is degraded by
aggrecanases. Aggrecan loss is a feature of cartilage disease. Early aggrecan loss is well documented and usually
precedes clinical symptoms, suggesting that it is the initiating step in cartilage pathology. Aggrecan loss precedes
collagen damage in explant culture, however it is not known whether inhibiting aggrecanases is sufficient to block
cartilage damage long-term. In contrast, other studies suggest that aggrecan is only lost after damage to the
collagen scaffold. These studies propose that clipping of the collagen scaffold may initiate aggrecan release; with
progressive degeneration and collagen clipping, more aggrecan is lost, until ultimately the scaffold is severely
damaged and aggrecan is severely depleted. Cartilage can only withstand a limited degree of collagen degradation
and any significant damage to the network is widely considered to be irreparable. It is unclear what role
aggrecanases and collagenases have in initiating and perpetuating cartilage damage. We have mice with aggrecan
resistant to aggrecanases and mice with inactive aggrecanase. We will also create mice with collagen resistant to
collagenase. We will use these mice to determine the contribution of collagenases and aggrecanases to the
initiation and progression of cartilage damage, in three models of joint disease. We will identify differences in
time of disease onset, rate of disease progression and disease severity. The results will show whether one or both
activities is important for the initiation & progression of joint disease. This will reveal whether single or
combination therapies are required for the management of arthritis. The research will inform the pharmaceutical
industry on directions for the development of new drugs to prevent joint disease.

Research achievements (from final report):
The ability of cartilage to protect the surface of bones from wear and tear is dependent upon the integrity of the
molecules collagen and aggrecan. In arthritis, the collagen scaffold is degraded by collagenases and aggrecan is
degraded by aggrecanases. Aggrecan loss is a feature of cartilage disease. Early aggrecan loss is well documented
and usually precedes clinical symptoms, suggesting that it is the initiating step in cartilage pathology. Aggrecan
loss precedes collagen damage in in vitro cultures, however it is not known whether inhibiting aggrecanases is
sufficient to block cartilage damage long-term. In contrast, other studies suggest that aggrecan is only lost after
damage to the collagen scaffold. These studies propose that clipping of the collagen scaffold by collagenases may
initiate aggrecan release; with progressive degeneration and collagen clipping, more aggrecan is lost, until
ultimately the scaffold is severely damaged and aggrecan is severely depleted. Cartilage can only withstand a
limited degree of collagen degradation and any significant damage to the network is irreparable. Because it is
unclear what role aggrecanases and collagenases have in initiating and perpetuating cartilage damage, we
engineered mutant mice in which the collagen scaffold is resistant to collagenases and/or the aggrecan is resistant
to aggrecanases. We are using these mice to determine the contribution of collagenases and aggrecanases to the
initiation and progression of cartilage damage, in three models of joint disease. Early comparisons of the mice
indicate that protecting the collagen scaffold is more likely to prevent cartilage erosion than protecting aggrecan.
The research will help prioritise strategies for blocking cartilage erosion in arthritic disease.

Expected future outcomes:
Although it is early days, we expect that the pharmaceutical companies will give greater consideration to therapies
that protect the collagen scaffold (collagenase inhibitors), rather than therapies that protect against aggrecan
degradation alone.

Name of contact:      A/Prof Amanda Fosang
Email of contact:     amanda.fosang@mcri.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:        400210                                            Start Year:      2006
CIA Name: Dr Richard Osborne                                       End Year:        2008
Main RFCD: Health Promotion                                        Total funding: $340,500.00
Admin Inst: University of Melbourne                                Grant Type: Standard Project Grant
Title of research award: Can patient self-management education programs improve outcomes of people with
osteoarthritis?
Lay Description (from application):
Arthritis is a very common disease associated with pain, disability and poor quality of life. An important way that
people with arthritis can deal with the disease is through using a variety of self-management behaviours and
coping strategies as well as becoming well informed about the best available treatments. A specific course was
developed in he US to help people self-manage. It has been available in Australia for 20 years through Arthritis
Foundations and has become their core business. Treatment guidelines used by doctors to treat people with
arthritis regularly recommend that patients should be referred to such courses. Although the course is widely
distributed, the evidence scientific evidence regarding its effectiveness is patchy, and some overviews suggest it is
not useful at all. Confusion exists regarding the value of the course. While treatment guidelines advise doctors to
refer patients to the program by very few GPs, Rheumatologist or Orthopaedic surgeons do refer. The proposed
study is a large controlled trial which will provide essential evidence to inform patients, doctors and policy makers
on the benefits of the course. It will involve people with well defined moderate to severe arthritis who have
consulted a surgeon or rheumatologist. People will be randomised to receive the intervention (two hours per week,
six session course including an 'arthritis self-help' book) will be compared with people in a control group (who
only receive the book without instruction). People will be followed for 1 year to see if the course improves quality
of life, health behaviours, and whether less health care resources (ie attendance at doctors or less medication use)
are used. The results of this study will be influential in determining government policy as the number of people
with chronic diseases like arthritis is rapidly growing and the acute healthcare system, including hospitals, are
poorly equipped to deal with this growing problem.

Research achievements (from final report):
Group-based patient education programs such as the Arthritis Self-Management Program (ASMP) are widely
applied and aim to impart skills for managing arthritis. Clinical guidelines indicate that people with osteoarthritis
(OA) should be referred to ASMPs as part of routine management, however the effectiveness of the program is
unknown. Previous research has mostly been conducted in the community setting among people with mild OA;
this project focused on people with moderate to severe OA who may be expected to benefit most from an effective
self-management intervention. We screened large numbers (n=1,123) of potentially eligible people across 7 public
and private Victorian hospitals. Of those screened, 208 declared they were not interested in such a course, 213
said they were unable to attend, 144 had insufficient English language, 117 were not contactable, and 254 were
ineligible for other reasons. Participation barriers included course format (group-based/6 weeks), scheduling,
location, family responsibilities or work commitments. Overall, the nature or structure of the course deterred 565
(50%) of those approached and only relatively well patients took part. Of the 187 eligible, only 120 were
randomized. While data analysis is continuing, preliminary analyses show that the ASMP had limited or no effect
on patient outcomes across many domains. This research provides insights into why people with arthritis do not
participate in ASMPs, with implications for the redesigning and planning of future programs. The ASMP may
only be suitable for some people in the outpatient setting and telephone, internet and multi-lingual programs are
likely to better reach patients.

Expected future outcomes:
This study will inform the development of new arthritis programs. We are currently developing a patient-focused
training program for health professionals to deliver self-management education and plan to develop an internet-
based intervention based on international protocols. Arthritis Foundations currently delivering education programs
will be encouraged to diversify their programs.

Name of contact:      Richard Osborne
Email of contact:     richard.osborne@deakin.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      454435                                             Start Year:       2007
CIA Name:      A/Pr Amanda J Fosang                               End Year:         2008
Main RFCD:     Rheumatology and Arthritis                         Total funding:    $207,500.00
Admin Inst:    University of Melbourne                            Grant Type:       Standard Project Grant


Title of research award: Regulation of ADAMTS-5 activity by keratan sulphate-binding exosites

Lay Description (from application):

Arthritis and musculoskeletal conditions are the predominant cause of disability in Australia. The burden of
arthritis is felt not only by patients, their families and carers, but also the labour market and the national economy.
There is a pressing need to identify new targets for design of inexpensive arthritis therapies. The TNF antagonists
have proved effective in managing rheumatoid arthritis (RA), but they are expensive, administered by injection,
and in general, only prescribed in Australia for patients who respond poorly to DMARDs. Their long-term
efficacy and safety is not yet determined. There are no treatments for osteoarthritis (OA), the disease that occurs
more frequently with age and is characterised by destruction of cartilage and aggrecan. New drugs that protect
against aggrecan breakdown are urgently needed for OA and they would also be valuable adjunct therapies to the
DMARDs for treatment of RA. We have discovered that the major aggrecan-degrading enzyme is ADAMTS-5.
ADAMTS-5 is, therefore, a potential target for arthritis therapies. Unfortunately, drugs targeting the active site of
ADAMTS-5 are predicted to fail, given the wide tissue distribution of ADAMTS-5, the high level of homology
between the active site of ADAMTS enzymes and matrix metalloproteinases (MMPs), and the notorious failure of
MMP active site inhibitors in clinical trials. The aim of this project is to determine whether ancillary domains of
ADAMTS-5 are a viable alternative target to the active site. We have evidence to suggest that keratan sulphate,
which is covalently attached to the aggrecan core protein, can modulate aggrecan cleavage by ADAMTS
enzymes. We aim to identify opportunities for developing antagonists that block keratan sulphate binding, or
keratan sulphate analogues that block enzyme binding to its substrate. The data will inform the pharmaceutical
industry on new directions for modulating aggrecanolysis by ADAMTS-5.

Research achievements (from final report):

The ability of cartilage to protect the surface of bones from wear and tear is dependent upon the integrity of a
proteoglycan called aggrecan. In the early stages of arthritis, aggrecan is degraded by metalloenzymes and lost
from cartilage. In 2005 we discovered that the metalloenzyme ADAMTS-5 is the major aggrecan-degrading
enzyme in mouse (Stanton et al, Nature, 2005). ADAMTS-5 is now a target for arthritis therapies. Unfortunately,
drugs targeting the active site of ADAMTS-5 are predicted to fail, given the wide tissue distribution of ADAMTS-
5, the high level of homology between the active site of ADAMTS enzymes and matrix metalloproteinases
(MMPs), and the notorious failure of MMP active site inhibitors in clinical trials. The aim of this project is to
determine whether ancillary domains of ADAMTS-5 are a viable alternative target to the active site. These
domains are implicated in enzyme-substrate binding. We have evidence to suggest that aggrecanase activity is
modulated by keratan sulphate (KS), which is covalently attached to the aggrecan core protein. To investigate
whether ADAMTS-5 ancillary domains bind KS, and whether this binding modulates activity, we expressed
mutant ADAMTS-5 proteins with progressive deletion of the C-terminal ancillary domains. The expression work
is complete, but the KS interaction studies are ongoing.

Expected future outcomes:

We expect to identify opportunities for developing ADAMTS-5 antagonists that block keratan sulphate binding,
or keratan sulphate analogues that block ADAMTS-5 binding to its substrate. This information will inform the
pharmaceutical industry on alternative approaches to ADAMTS-5 catalytic inhibitors.

Name of contact:       A/Prof Amanda Fosang
Email of contact:      amanda.fosang@mcri.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      454686                                        Start Year:            2007
CIA Name:      Prof Kim L Bennell                            End Year:              2008
Main RFCD:     Rehabilitation and Therapy: Occupational and Physical                Total funding: $264,250.00
Admin Inst:    University of Melbourne                       Grant Type:            Standard Project Grant


Title of research award: Reducing knee load and slowing disease progression with conservative interventions in
knee osteoarthritis.

Lay Description (from application):

Knee arthritis is a painful, disabling, costly condition particularly affecting the elderly. As there is presently no
cure for arthritis, interventions that slow progression of the disease will reduce the personal and societal burden of
arthritis. Recently it has been postulated that specific exercise that targets how the muscles are controlled by the
nervous system may have greater disease-modifying effects than exercise aimed at strengthening the muscles.
Data are beginning to highlight the complexity of muscle strategies adopted by the nervous system to compensate
for joint derangement in knee arthritis. It is our contention that there may be specific strategies that provide more
optimal knee joint loading in relation to slowing disease progression. The first part of this project is to investigate
knee control in people with knee arthritis and to evaluate whether this influences disease progression. This will
provide the basis for refinement and optimisation of rehabilitation interventions for this patient group. The second
part of this project will investigate whether strengthening the hip muscles in patients with knee arthritis influences
knee load and hence disease progression. Hip muscle strengthening is currently not routinely included as part of
the management of knee arthritis. If the results of this project find it to be effective, then hip muscle strengthening
can be recommended for treating knee arthritis.

Research achievements (from final report):

This study comprised two parts; one investigated knee muscle activation patterns in people with knee
osteoarthritis and their relationship to disease progression and the other was a clinical trial that investigated the
effectiveness of hip strengthening exercises on knee joint load and disease symptoms in 89 people with painful
knee osteoarthritis. The results suggest that the way the muscles are activated may play a role in influencing the
amount of knee cartilage lost and hence the risk of disease progression. This has implications for the development
of novel physiotherapy treatments for knee osteoarthritis. A structured home program of hip strengthening
exercises supervised by a physiotherapist was effective at reducing pain and dysfunction but did not reduce knee
load. This provides information that assists in evidence-based recommendations for the conservative non-drug
management of knee osteoarthritis.

Expected future outcomes:

The results of this study will be published in peer-reviewed leading rheumatology journals and will be the subject
of conference presentations. The study will contribute to clinical guidelines for the management of knee
osteoarthritis and the development of novel interventions for knee osteoarthritis that may reduce pain and slow
disease progression

Name of contact:       Prof Kim Bennell
Email of contact:      k.bennell@unimelb.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      509310                                         Start Year:         2008
CIA Name:      Dr Kerrie Sanders                              End Year:           2008
Main RFCD:     Medical and Health Sciences not elsewhere classified               Total funding: $102,850.00
Admin Inst:    University of Melbourne                        Grant Type:         Standard Project Grant


Title of research award: Does an Annual High Dose Vitamin D Supplement Decrease Healthcare Utilisation in
Older Women?

Lay Description (from application):

The shorter bleaker days of winter can cause a vitamin D deficiency in Australian women, increasing their risk of
osteoporosis and broken bones including hip fracture. New research suggests that the low winter levels of the
vitamin may not be good for us in many ways and the NHMRC is funding a Geelong-based study to determine if
Austrlia's elderly can improve their overall health by taking a once-a-year dose of vitamin D tablets.

Research achievements (from final report):

Recent research suggests that higher levels of vitamin D in your blood may provide protection from many
disorders such as diabetes, osteoporosis, depression and certain types of cancer. This project represents the first
international study to investigate this hypothesis using a randomised, placebo-controlled clinical trial. The
hypothesis was that older women supplemented annually for 3 to 5 years with a high oral dose of vitamin D3
(500,000 IU) would use fewer healthcare services than those given placebo (dummy) tablets. The preliminary
analysis using data from Medicare Australia suggests there is no difference between the groups and that the
women randomised to vitamin D used the same number of Medicare services as women receiving placebo
(vitamin D group: 28.5 and placebo group: 28.0 Medicare services per person per year). The age of participants
did not differ between the groups (vitamin D: 76.8 years and placebo: 76.7 years). In the year prior to
commencing the study medication the women used an average of 18.5 services per person (vitamin D group: 18.6
and placebo group: 18.5). These results also suggest that women aged 70+ years had a 1.5 fold increase in the
average number of healthcare service/visits they used each year over a 2 to 3 year period and that this increase did
not differ between those given vitamin D and placebo.

Expected future outcomes:

Further analysis of the data will determine the cost of healthcare services between the vitamin D and placebo
groups to determine if there is a significant difference in the type of health services used and the total cost of
health service utilisation between the two groups. The data will be analysed by age group using 70-74; 75-79; and
80+ years and stratified by fracture (yes/no).

Name of contact:      A/Prof Kerrie Sanders
Email of contact:     kerrie@barwonhealth.org.au
                            NHMRC Research Achievements - SUMMARY
University of New South Wales

Grant ID:      157080                                        Start Year:       2001
CIA Name: Dr Judith S Walker                                 End Year:         2004
Main RFCD: Pharmacology not elsewhere classified             Total funding: $135,000.00
Admin Inst: University of New South Wales                    Grant Type: Standard Project Grant
Title of research award: Opioids as a new therapy for inflammatory arthritis: immunopharmacological
mechanisms
Lay Description (from application):

Arthritis is a chronic inflammatory disorder characterized by joint pain, swelling and stiffness. In fact, 69% of
patients present with radiographic erosions and joint space narrowing during the first three years of the disease
and it is insufficiently appreciated that patients with rheumatoid arthritis may have a 5-year mortality similar to
patients with cardiovascular or neoplastic disease. Prevention of disability and death is the ultimate goal of
treatment. However, no cure is yet available. Instead, current treatment is aimed at relieving symptoms and
improving functional performance. There is now a growing recognition that patients with rheumatoid arthritis
require more agressive treatment early in the disease, before the development of erosions and deformity. My work
has shown for the first time that opioid drugs that act via kappa (k) receptors in the periphery are able to
ameliorate the incidence and severity of disease symptoms in rat adjuvant arthritis. Histological and radiological
analysis reveals a significant, beneficial effect on joint pathology. The present proposal seeks to build upon this
basic information gained in rats into the anti-inflammatory mechanisms of opioid action. I will now apply my
expertise to extend this research in animals to human tissues. I am able to combine multiple techniques to carry
out a systematic and rigorous study on human synovium from arthritis patients. This work aims to find out why
opioids have anti-arthritic actions and might potentially lead to potent, less toxic and less expensive new therapies
for arthritis and increase our understanding of the pathogenesis of arthritis.

Research achievements (from final report):
The aim of these studies was to assess the therapeutic potential of opioids in the treatment of adjuvant arthritis in
rats, and to investigate the immunopharmacological mechanisms by which opioids mediate their anti-
inflammatory effects. The antinociceptive and anti-inflammatory properties of the novel peripherally selective k-
opioid ADL 10-0116 were examined in the adjuvant arthritis model and compared to asimadoline. Treatment with
ADL 10-0116 significantly reduced the pooled severity index - paw swelling, radiography and histology - by as
much as 69%. The anti-inflammatory effect of ADL 10-0116 was similar to that obtained with asimadoline.
Antinociceptive effects showed a dose-dependant increase in paw pressure threshold compared to control animals.
The optimum anti-inflammatory dose (10 mg/kg/day) was much lower then the optimum analgesic dose (40
mg/kg/day). The readily clinically available opioid oxycodone was also found to attenuate adjuvant induced
arthritis in rats by as much as 50%. These anti-inflammatory effects were significantly enhanced when oxycodone
was administered locally (i.pl) in comparison to distant administration (i.p), indicating a peripheral site of action.
This was confirmed by administration of the opioid antagonist naloxone methiodide. - antagonist MR2266 dose-
dependently inhibited the anti-inflammatory effects of oxycodone (5 mg/kg; i.pl).kTreatment with the - receptors
in the periphery.kThese results indicate that oxycodone mediates its anti- inflammatory effects via opioid-treated
rats.kHistomorphometry showed significantly fewer cells positive for the chemokines CCL3 and CX3CL1, in
arthritic joints from Our findings suggest that peripherally acting opioid agonists may lead to improved anti-
inflammatory activity compared to standard non-steroidal anti-inflammatory drugs, partly by inhibiting
chemokines. This raises the possibility of novel combination therapies incorporating anti-inflammatory opioids in
arthritis.

Expected future outcomes:
Further experiments aimed at addressing the role of opioids in attenuation of chemokine-dependent inflammatory
cell migration to inflamed joints need to be pursued. In addition, examination of novel peripherally active k opioid
agonists needs to be initiated in the human disease setting.

Name of contact:       Michael Grimm
Email of contact:      M.Grimm@unsw.edu.au
                           NHMRC Research Achievements - SUMMARY

Grant ID:      222870                                           Start Year:      2003
CIA Name:      Dr Kieran F Scott                                End Year:        2005
Main RFCD:     Medical Biochemistry: Proteins and Peptides      Total funding:   $525,000.00
Admin Inst:    University of New South Wales                    Grant Type:      Standard Project Grant


Title of research award: The Mechanism of Action of Secreted Phospholipase A2 in Inflammation

Lay Description (from application):

Secretory phospholipase A2 (sPLA2) is an important mediator of inflammation and is clinically associated with
the onset and severity of several immune-mediated diseases including arthritis, asthma, atherosclerosis, psoriasis
and recently prostate cancer. These are complex diseases which are poorly understood. We have shown that
sPLA2 can by itself and in combination with inflammatory cytokines modulate signalling pathways in cells
derived from the joints of patients with arthritis to upregulate inflammatory molecules. How this happens is
completely unknown. We plan to work out how this enzyme does this. We have also developed small cyclic
peptide inhibitors of sPLA2 which potently block the function of the enzyme in these cells. We plan to determine
how this happens and if these inhibitors are effective at blocking inflammation and arthritis. The proposal may
identify new mechanisms by which secreted factors upregulate inflammation in human cells and may lead to the
discovery of new ways to intervene to block these pathways.

Research achievements (from final report):

Four key findings from this grant provide insights into how secreted phospholipase A2 (sPLA2) proteins may be
usefully targeted to treat certain inflammatory conditions such as rheumatoid arthritis (RA) and some cancers.
First, we have found that sPLA2 amplifies proinflammatory pathways in cells from the joints of patients with RA
by new mechanisms that do not need the enzyme activity of the protein. Blocking these new pathways may be
better than blocking enzyme activity. Second, we have learned more about how sPLA2 gets into cells and
generated new ideas about how sPLA2 might be working. Third, our new inhibitors are orally absorbed and well
tolerated, suggesting they have the chemical properties that may make them useful oral medicines. Fourth we have
worked out how several sPLA2 inhibitors bind to sPLA2.This information will help us design more potent and
selective inibitors. Together these findings suggest our efforts to develop new treatments for inflammation and
cancer are worth continuing.

Expected future outcomes:

These findings are encouraging because they strengthten the evidence that our approach to developing a new
treatment approach to immune-mediated inflammation and certain cancers based on inhibition of secreted
phospholipase A2 continue to valid and therefore should be pursued.

Name of contact:      Dr Kieran Scott
Email of contact:     kieran.scott@unsw.edu.au
                            NHMRC Research Achievements - SUMMARY

University of Queensland

Grant ID:      142958                                           Start Year:       2001
CIA Name:      Dr Mark R Forwood                                End Year:         2003
Main RFCD:     Orthopaedics                                     Total funding:    $300,000.00
Admin Inst:    University of Queensland                         Grant Type:       Standard Project Grant


Title of research award: Prostaglandin G/H synthase is a key regulator of bone remodelling and skeletal
adaptation

Lay Description (from application):

Knowledge of the biology underlying bone formation is important for developing novel approaches to stimulate
new bone formation in skeletal diseases associated with ageing or disability, or for maintenance of new bone
around orthopaedic or dental implants. The discovery that a prostaglandin enzyme (PGHS-2) is a key factor in
activity-related bone formation and normal bone turnover, as well as a pharmacological target for reducing
inflammation, has considerable clinical significance. Specific inhibition of PGHS-2 by recent anti-inflammatory
drugs avoids formation of gastric ulcers, but their influence on normal bone remodelling and fracture repair is not
known and must be investigated. Many such inhibitors are in advanced clinical trials, but their effect on bone
metabolism has not been published. This project is important because it employs novel experimental models to
advance our knowledge of prostaglandin biology in skeletal adaptation, and elucidates important clinical
consequences for specific inhibition of PGHS-2 in the skeleton. This project will investigate the regulation of
prostaglandin production by PGHS enzymes following mechanical loading in vivo. It will use cell, molecular and
histochemical techniques to determine if the genes that regulate the enzymes are influenced by mechanical stimuli,
and if they are dependent on other molecules, associated with structural proteins (stress fibres) within the cell. It
will investigate if inhibition of PGHS-2 by antiinflammatory drugs or stress-fibre inhibitors, depresses normal
bone turnover and healing responses. The outcome of these experiments could indicate new approaches to
stimulate bone formation, preserve bone mass, or minimise adverse skeletal effects of anti-inflammatory
treatments related to orthopaedic or dental procedures.

Research achievements (from final report):

The experiments showed that PGHS-2 (or COX-2) gene expression (normally related to inflammation) is
increased in bone tissue following loading. It also provided experimental evidence that PGHS-2 inhibition reduces
bone turnover which can prevent menopause related bone loss. This was shown to be related to decreases in
osteoclast surface and activity - the cells that remove bone. PGHS-2 inhibitors (anti-inflammatory drugs) also
slowed the remodelling and consolidation of woven bone on the periosteal surface following loading. This would
lead to increased healing time for fractures, but would not jeopardise the strength of those healing fractures. The
findings above suggest that there is a clinical implication for COX-2 inhibition in terms of regulating bone
turnover, but this has not yet been translated into a direct clinical outcome.

Expected future outcomes:

Evidence that new antinflammatory drugs not only reduce inflammation, but may have a role in managing and
regulating bone diseases associated with rapid bone loss, will be investigated. The role of COX-2 in bone biology
is being pursued in mice producing excess levels of this enzyme to study whether this exacerbates conditions of
bone loss or enhances adaptive mechanisms associated with loading

Name of contact:      Mark Forwood
Email of contact:     m.forwood@uq.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      252968                                           Start Year:       2002
CIA Name:      A/Pr Stephen M Taylor                            End Year:         2003
Main RFCD:     Basic Pharmacology                               Total funding:    $160,000.00
Admin Inst:    University of Queensland                         Grant Type:       Development Grant


Title of research award: Developing Anti-inflammatory drugs based on inhibition of a Human Enzyme

Lay Description (from application):

Human secretory phospholipases A2 have been associated with inflammatory diseases for many years, yet very
few truly potent inhibitors of the human enzymes sPLA2 (isoforms IIa, V or X) are known due to a range of
problems relating to the lipid nature of substrates, unavailability of enzymes, enzyme assays that do not correlate
with in vivo data. Although there remains controversy about which enzyme is responsible in vivo for degrading
membrane phospholipids to inflammatory mediators like arachidonate, PAF, prostaglandins, leukotrienes, etc.
there is a consensus that blockade of phospholipid metabolism would represent a major advance on NSAIDs as
antiinflammatory agents. No sPLA2-IIa inhibitor is available yet in man. We aim to create an attractive data
package showing proof of concept for a potent new type of antiinflammatory drug. This data will give us an
improved negotiating position in our commercialisation of a new drug with potential multi-billion dollar markets
as diverse as arthritis, asthma, reperfusion injury, organ transplantation and many other currently intractable
human ailments

Research achievements (from final report):

This project aimed to design, synthesize & evaluate new inhibitors of human non-pancreatic secretory
phospholipase A2 type IIa (sPLA2), implicated in many inflammatory diseases. Chemistry, biochemistry &
pharmacology were used to validate sPLA2 as a target and to identify lead molecules. A variety of new inhibitors
of the enzyme were designed and tested for activity and several with nanomolar levels of potency were found.
Testing in animal models of inflammatory disease revealed that one lead compound had anti-inflammatory
activity in models of rheumatoid arthritis, inhibited rat uterine contractions and ischemia reperfusion injury. The
data also showed that the drug was orally bioavailable, with detectable levels apearing in the blood following oral
administration. The results suggest that this new class of drug has prominent anti-inflammatory activity which
may translate into new therapies in humans if developed to the clinic.

Expected future outcomes:

The results will enable the design of improved compounds for testing in a variety of models of human
inflammatory disease. The validation of a variety of animal models of inflammatory disease sensitive to this new
class of drugs has been achieved broadening the applications of these drugs.

Name of contact:      Steve Taylor
Email of contact:     s.taylor@uq.edu.au
                           NHMRC Research Achievements - SUMMARY

Grant ID:      210237                                           Start Year:      2002
CIA Name:      Prof Ranjeny Thomas                              End Year:        2004
Main RFCD:     Autoimmunity                                     Total funding:   $140,000.00
Admin Inst:    University of Queensland                         Grant Type:      Standard Project Grant


Title of research award: Induction of antigen-specific tolerance through inhibition of RelB function in dendritic
cells

Lay Description (from application):

This proposal builds on preliminary data showing the possibility that responses of the immune system to antigens
can be suppressed by modifying cells known as dendritic cells using an inhibitory drug. The drug appears to be
able to control the ability of dendritic cells to educate the immune system about antigens. When antigens
presented continuously are harmful to the immune system, they produce diseases such as rheumatoid arthritis and
allergies. The experiments to be undertaken specifically look at means to prevent and reverse diseases like
rheumatoid arthritis through the use of dendritic cells.

Research achievements (from final report):

Dendritic cells (DC) are a key component of the immune system and are involved in regulation of innate and
acquired immunity. These cells capture, process and present antigens to T cells, and have been implicated in
autoimmune disease as well as other diseases of the immune system such as allergy, immunodeficiency, transplant
rejection, persistent viral infection and cancer. We have carried out in vitro and in vivo experiments that provide
evidence in mice of the capacity of DC modified with an inhibitor of NFkB activation, to suppress existing
immune responses in an antigen-specific way. Data indicate that the ability of DC to induce T cell activation or
tolerance can be controlled by manipulation of a protein known as RelB in DC. Thus, mouse DC, generated in the
presence of a soluble inhibitor of NFkB (modified DC) and exposed to antigen, prevent priming, and also suppress
a previously primed immune response and arthritis in mouse models. This tolerance is antigen-specific, and
dependent on the dose of administered DC. In vitro studies of modified human blood DC demonstrate that the
cells have a similar phenotype and in vitro functional capacity as the modified mouse DC. These results suggest
that future treatment of autoimmune disease with modified dendritic cells may provide an effective, and antigen
specific solution to controlling the disease in affected individuals. This modified DC platform technology has
potential application in a number of diseases where tolerance is broken, including autoimmune disease, allergy,
transplantation and graft vs. host disease (GVHD).

Expected future outcomes:

Modified DC are in development for tolerising immunotherapy in a phase I clinical trial. If successful they will be
further developed for applications in autoimmune disease.

Name of contact:      Rthomas@Cicr.Uq.Edu.Au
Email of contact:     agautam@cicr.uq.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      210261                                            Start Year:      2002
CIA Name:      Dr Alan I Cassady                                 End Year:        2004
Main RFCD:     Gene Expression                                   Total funding:   $225,000.00
Admin Inst:    University of Queensland                          Grant Type:      Standard Project Grant


Title of research award: Osteoclast-Specific Gene Regulation

Lay Description (from application):

Osteoporosis is a pathological loss of bone that affects many Australians. It occurs because of an excessive release
of calcium from bone that is caused by the overactivity of the cells that break down bone, osteoclasts. We have
studied two genes that are involved in the way these cells work and by a close examination of the the way they are
regulated we hope to understand how osteoclasts are derived and how their activity is controlled. In particular we
will look at two newly dicovered osteoclast regulators called PPAR-gamma and PPAR-delta. These offer the
opportunity for the development in the future of new, alternative drugs for the treatment of osteoporosis.

Research achievements (from final report):

Osteoclasts are the cells responsible for the normal processes of damaged bone removal and bone remodelling but
in diseases such as osteoporosis the over-activity of osteoclasts results in weak bones. We have been studying the
control of osteoclast genes in order to understand the mechanisms that govern their activity. In this project we
studied a characteristic osteoclast marker gene called "TRAP" and have identified DNA structures within the gene
that govern the operation of the gene. This pattern of regulation may apply more generally to other osteoclast
genes. In addition we have characterized previously unreported mouse and human gene structures that will govern
the sites at which this gene is expressed. elta in regulating these genes.delta activity, carbaprostacyclin, also up-
regulates the expression of the osteoclast marker genes including the calcitonin receptor and MMP-9, implicating
PPAR-delta which others have implicated in osteoclast cell activity is expressed in osteoclasts and is up-regulated
by the pathological bacterial product LPS. The stimulator of PPAR-dWe have found that the steroid hormone
receptor PPAR- elta in bone remodelling.delta gene in osteoclasts without generalized effects on mouse
development which are known to occur with a standard knockout strategy. Using this approach we can make a
more comprehensive assessment of the role of PPAR-dWe have generated new transgenic mouse lines to be used
to knockout genes of interest specifically in osteoclasts. These utilize the control regions of the osteoclast-
expressed TRAP and cathepsin K genes to drive expression of the Cre enzyme. When these mice are crossed with
transgenic mice in which the target gene of interest is marked by "loxP" sites then the gene will be excised. This
will permit us to examine the biology of gene knockout of the PPAR-

Expected future outcomes:

The characterization of PPAR-responsive elements in osteoclast-expressed genes will proceed to determine if
PPAR-delta in particular has direct or indirect effects on osteoclastogenesis. The PPAR-delta conditional
knockout mouse is under investigation for phenotypic effects on bone development, structure and turnover.

Name of contact:       Alan Cassady
Email of contact:      I.Cassady@imb.uq.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      252879                                            Start Year:      2003
CIA Name:      Prof Ranjeny Thomas                               End Year:        2004
Main RFCD:     Autoimmunity                                      Total funding:   $140,000.00
Admin Inst:    University of Queensland                          Grant Type:      Standard Project Grant


Title of research award: Migration and differentiation of dendritic cells and monocytes in inflammatory arthritis

Lay Description (from application):

Dendritic cells and monocytes are of critical importance to the development and persistence of inflammatory
disease in rheumatoid arthritis. Blocking this process at key strategic intervention points is a major focus of
research to improve disease treatment. These studies examine the critical processes and molecules that control the
entry of these cells to the joint in mice, and the derivation of cells that contribute directly to bone damage in the
disease.

Research achievements (from final report):

Given the importance of cells of the mononuclear phagocyte system in the pathogenesis of RA through antigen
presentation, inflammatory cytokine and chemokine production, and bone erosion, these studies were designed to
contribute information on the basic mechanism of their recruitment and homing and contribution to the
inflammatory process in vivo. Such work is essential for development of therapeutics targeting these migratory
pathways. Furthermore, the novel model systems developed for this project provide the first opportunity to
perform detailed cDNA expression profiling on DC populations. The array infrastructure provided by associate
investigator David Hume, is the most extensive available for the study of mononuclear phagocyte biology. During
the granting period we examined recruitment and homing of dendritic cells, monocytes and neutrophils to
inflamed joints and lymphoid organs in mice. We used mice transgenic for the green fluorescent protein expressed
by the c-fms promoter to examine the differentiation and expansion DC in vivo. Finally we carried out cDNA
expression profiling on immunogenic and tolerogenic DC, generating much novel information on genes impacting
on tolerance induced by antigen presenting cells.

Expected future outcomes:

We aim to demonstrate mechanisms of recruitment of DC and neutrophils to lymphoid organs under conditions of
immunity and tolerance, and we aim to understand the contribution of various genes induced or suppressed under
conditions of tolerance to the mechanisms of tolerance.

Name of contact:       Rthomas@Cicr.Uq.Edu.Au
Email of contact:
                            NHMRC Research Achievements - SUMMARY

Grant ID:      301244                                            Start Year:      2004
CIA Name:      Prof Ranjeny Thomas                               End Year:        2004
Main RFCD:     Cellular Immunology                               Total funding:   $160,000.00
Admin Inst:    University of Queensland                          Grant Type:      Development Grant


Title of research award: Phase I clinical trial of autologous dendritic cells to induce antigen-specific tolerance

Lay Description (from application):

We have previously generated modified dendritic cells in mice with the ability to suppress immune responses once
they have started. This project will develop the dendritic cell vaccine as a platform technology for human clinical
use. We aim to demonstrate, in a phase I clinical trial, the capacity of modified human autologous dendritic cells
to suppress the immune response to a model antigen in a group of healthy volunteers and a group of patients with
rheumatoid arthritis taking drugs for their disease

Research achievements (from final report):

Dendritic cells (DC) are a key component of the immune system and are involved in regulation of innate and
acquired immunity. These cells capture, process and present antigens to T cells, and have been implicated in
autoimmune disease as well as other diseases of the immune system such as allergy, immunodeficiency, transplant
rejection, persistent viral infection and cancer. We have carried out in vitro and in vivo experiments that provide
evidence in mice of the capacity of DC modified with an inhibitor of NFkB activation, to suppress existing
immune responses in an antigen-specific way. Data indicate that the ability of DC to induce T cell activation or
tolerance can be controlled by manipulation of a protein known as RelB in DC. Thus, mouse DC, generated in the
presence of a soluble inhibitor of NFkB (modified DC) and exposed to antigen, prevent priming, and also suppress
a previously primed immune response and arthritis in mouse models. This tolerance is antigen-specific, and
dependent on the dose of administered DC. In vitro studies of modified human blood DC demonstrate that the
cells have a similar phenotype and in vitro functional capacity as the modified mouse DC. This project will
developed human modified DC as a platform technology for human clinical use. During the granting period we
produced modified human dendritic cells (DC) to GLP standard, developed in vitro assays and specific operating
procedures for QA and antigen loading of the modified DC, tested toxicity of modified DC in mice and wrote and
submitted a clinical trial protocol to our institutional ethics committee.

Expected future outcomes:

We aim to demonstrate, in a phase I clinical trial, the capacity of modified human autologous dendritic cells to
suppress the immune response to a model antigen in a group of healthy volunteers and a group of patients with
rheumatoid arthritis taking drugs for their disease.

Name of contact:      Rthomas@Cicr.Uq.Edu.Au
Email of contact:     agautam@cicr.uq.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      143109                                        Start Year:           2001
CIA Name:      Dr Allison R Pettit                           End Year:             2005
Main RFCD:     Cell Development (incl. Cell Division and Apoptosis)                Total funding: $223,268.32
Admin Inst:    University of Queensland                      Grant Type:           CJ Martin Fellowship


Title of research award: The role of T cell expression of receptor-activator of NFkB ligand (RANKL) in the
pathogenesis of rheumatoid arthritis bone erosion

Lay Description (from application):

No available Lay Description

Research achievements (from final report):

Research undertaken during the tenure of this Fellowship prominently contributed to the delineation of the cellular
and molecular mechanisms of bone destruction in inflammatory arthritis. Bone destruction is a detrimental
outcome in many diseases, including rheumatoid arthritis and osteoporosis. It is associated with poor prognosis
and significantly contributes to morbidity. We definitively demonstrated that osteoclasts (cells that remove bone
in normal bone remodelling) are primarily responsible for bone destruction in inflammatory arthritis. Additionally,
we provided compelling evidence supporting that the regulatory factor RANKL (receptor activator of NF-κB
ligand) is the critical and potentially rate limiting signal driving the aberrant formation of osteoclasts and
subsequently bone destruction in inflammatory arthritis. These studies provided compelling evidence to support
that RANKL is a promising therapeutic target for the prevention of bone destruction in inflammatory arthritis and
many other diseases that have associated-bone destruction. To better understand how RANKL expression is
controlled, we examined regulation of RANKL gene expression in T cells, a relevant source of RANKL in
inflammation. The data indicated that NFAT (nuclear factor of activated T cell) gene regulatory factors may be
important regulators of RANKL expression in T cells. Importantly, NFAT factors have also been shown to be
important regulators of osteoclast development. Therefore, considering that NFATs potentially contribute to
osteoclast formation at mutliple points in the pathyway, strategic blockade of the NFAT gene regulatory factors
may provide a powerful strategy for preventing inflammation-associate bone destruction.

Expected future outcomes:

Clinical trials are currently underway to determine the safety and efficacy of therapies that block that action of
RANKL. Successful therapies will significantly reduce the economic and social impact of musculoskeletal
diseases such as rheumatoid arthritis and osteoporosis.

Name of contact:       Allison Pettit
Email of contact:      a.pettit@imb.uq.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      157085                                        Start Year:    2001
CIA Name: Prof Paul W Hodges                                 End Year:      2005
Main RFCD: Motor Control                                     Total funding: $165,000.00
Admin Inst: University of Queensland                         Grant Type: Research Fellowship
Title of research award: Physiology and pathophysiology of trunk control mechanisms

Lay Description (from application):
The overall aim of this series of experiments is to understand how the spine is controlled and how this changes in
disease. Altered control has been identified in people with low back pain, yet we still know very little about the
normal mechanisms for protection and support of the spine. Back pain is a common affliction that affects about
5% of Australians each year and is the most common and expensive work-related injury in western society. An
understanding of normal control and the mechanism of dysfunction is critical for identification of risk factors and
development of strategies for rehabilitation and prevention. The experiments are divided into two series. The first
series addresses normal spinal control. The questions to be asked deal with how the brain copes with the challenge
of using trunk muscles for breathing and spinal control at the same time, how the activity of the trunk muscles is
affected by input from sensory receptors in the joints, ligaments and muscles of the spine, and whether intra-
abdominal pressure can support the trunk. The second series deals with clinical populations. The first aim is to
identify whether people with respiratory diseases use trunk muscles for spinal control and breathing at the same
time. If they cannot, we predict that they will be more prone to low back pain. We will test this in a large study of
incidence of low back pain in people with and without respiratory disease. The second study will investigate the
pelvic floor muscles which are important for continence and assist with spinal control. We will investigate
whether people with incontinence have poor spinal control and whether this leads to back pain. The final
experiment will identify whether people with low back pain interpret sensory information from the spine
differently. By answering these questions we hope to intervene in the enormous personal, social and economic
consequences of LBP which affects between 60-90% of the population at some stage in their life.

Research achievements (from final report):
This project involved a series of clinical and experimental studies to investigate the strategies used by the nervous
system to control the spine and changes that occur in pain and disease. The studies provide a range of important
outcomes that can guide the management and prevention of low back and pelvic pain. Key outcomes include: .
Injury to a disc in the lumbar spine causes unexpectedly rapid atrophy of back muscles. This is likely to
compromise control of the spine. These data provide a physiological rationale for exercise in back pain. This study
was awarded the ISSLS prize, the premier international award for spine research. . A novel series of experiments
studied the consequences of competition between the contribution of the spinal muscles to control of movement
and stability and the contribution of these muscles to respiration and continence. The results show that increased
demand for breathing and continence, due to disease or a function-specific challenge (e.g. breathing increased
carbon dioxide, increased bladder volume), is associated with compromised control of the spine. This was linked
to epidemiological data that showed an increased risk for development of back pain in individuals with breathing
difficulties and incontinence. . Studies also show that low back pain, when induced experimentally, leads to
dramatic changes in coordination of spinal muscles. The studies provide evidence of factors that compromise
control of the spine. These findings have led to changes in evaluation and management of back pain. Ongoing
work aims to assess the efficacy of these refined interventions.

Expected future outcomes:
The studies completed in this program provide a basis for a range of strategies that have the potential to refine the
management and prevention of low back and pelvic pain. Future studies are required to determine the magnitude
of the clinical effect.

Name of contact:       Paul Hodges
Email of contact:      p.hodges@uq.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      157203                                        Start Year:          2001
CIA Name:      Prof Paul W Hodges                            End Year:            2005
Main RFCD:     Rehabilitation and Therapy: Occupational and Physical              Total funding: $480,000.00
Admin Inst:    University of Queensland                      Grant Type:          NHMRC Research Fellowship


Title of research award: Research Fellowship (2001-2002)/Senior Research Fellowship (2003-2005)

Lay Description (from application):

No available Lay Description

Research achievements (from final report):

The work undertaken during the 5 years of the Research Fellowship involved investigation of the physiology and
pathophysiology of movement control in people with a range of conditions including low back pain, respiratory
disease and incontinence. Using physiological and epidemiological methods in human and animal experiments the
studies provide novel data of a range of factors that challenge the control of the trunk muscles, and have led to the
development of intervention strategies. Examples include: . Animal experiments showed that injury to an
intervertebral disk leads to rapid atrophy of the deep back muscles. . Evaluation of a large population of Australian
women showed that incontinence and breathing disorders are a risk factor for the development of back pain. Other
studies suggest that this may be due to competition between the contribution of the trunk muscles to spinal
control, continence and breathing. . Studies show that pain and fear of pain lead to complex changes in the control
of the trunk muscles. This suggests that patients who are fearful of injury control movement as if they have pain.
These studies point to changes in control of the muscles, rather than strength and endurance. . Similar changes in
muscle control were also identified in people with neck pain, knee pain and shoulder pain. . Clinical trials of
exercise strategies based on these studies provided evidence of clinical efficacy in people with back, neck and
knee pain. Other studies showed that the improvement in symptoms is associated with improvements in muscle
control.

Expected future outcomes:

The completed studies have provided evidence of a range of factors that are candidates as risk factors for the
development and recurrence of low back pain. Current and future work aims to determine whether clinical
interventions can change these factors and improve the long term prognosis for those at risk for back pain.

Name of contact:      Paul Hodges
Email of contact:     p.hodges@uq.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      252771                                        Start Year:           2003
CIA Name:      Prof Gwendolen A Jull                         End Year:             2005
Main RFCD:     Rehabilitation and Therapy: Occupational and Physical               Total funding: $225,000.00
Admin Inst:    University of Queensland                      Grant Type:           Standard Project Grant


Title of research award: Physiological mechanisms of efficacy of cervical flexor muscle retraining

Lay Description (from application):

Neck pain is a significant problem in society and its frequency is beginning to match the proportions of back pain,
probably reflecting our increasingly sedentary lifestyles. Several problems have been identified in the muscle
system in persons who suffer from neck pain. Therapeutic exercise has been found to have benefit in preventing
and relieving pain and improving the neck function. Currently there are several, quite different methods of
exercise and there is controversy regarding how therapeutic exercise works. It has been argued that parameters
such as changes in muscle strength, endurance, joint position sense or muscle coordination may be responsible for
the clinical efficacy. It is difficult to disentangle the effective component of exercise strategies and thus prescribe
the most effective exercise strategies. This series of experiments will evaluate the physiological factors that
change with a specific exercise intervention and to compare different exercise modalities in order to identify the
most effective means to induce these changes. Cervical muscle training, using a proven exercise intervention
strategy for chronic neck pain and headache, has been chosen as the model to investigate these questions. This
exercise strategy has been chosen not only because it has been shown to be effective, but also because it does not
conform to contemporary rationales for strength or endurance training. Thus while effective in relieving pain, it is
unlikely to produce changes in these parameters. Thus other mechanisms are likely to be responsible for the
clinical change. This research stands to make a significant contribution to exercise therapeutics by identifying the
effective components of different exercise methods and investigating the pain relieving effects of the specific
exercise. This knowledge will lead to the construction of a research based exercise program for neck pain patients,
rather than have the current situation of often arbitrary choice of exercise.

Research achievements (from final report):

Neck pain is a significant problem in society and its frequency is beginning to match the proportions of low back
pain. Changes in neck muscle function have been identified in people with neck pain and therapeutic exercise
programs designed to address these deficits, have demonstrated efficacy in relieving neck pain. However, several,
quite different methods of exercise have been proposed and there is controversy regarding optimal exercise
selection and how exercise achieves pain relief. It has been argued variously that parameters such as changes in
neck muscle strength, endurance, joint position sense or muscle coordination may be responsible for the clinical
efficacy. A series of experiments was undertaken to evaluate the effect of various exercise regimes on
physiological measures of neck muscle function which are known to be impaired in people with neck pain. The
results indicated that specificity in training is required to most effectively change neck muscle impairment. This
knowledge has translated to the construction of a research based, progressive exercise program for neck pain
patients, rather than the current situation of an arbitrary choice of exercise. The efficacy of this exercise approach
is currently being tested in a randomised clinical trial for neck pain following a whiplash injury.

Expected future outcomes:

The results of the research will guide further development of specific therapeutic exercise interventions for the
management and prevention of neck pain, based scientifically on the physiological responses to training.

Name of contact:       Gwendolen Jull
Email of contact:      g.jull@uq.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      252811                                            Start Year:      2003
CIA Name:      Prof David P Fairlie                              End Year:        2005
Main RFCD:     Enzymes                                           Total funding:   $420,000.00
Admin Inst:    University of Queensland                          Grant Type:      Standard Project Grant


Title of research award: Design And Development Of Small Molecules To Regulate Protease Activated
Receptor Type 2

Lay Description (from application):

A new class of proteins have been discovered on the surface of cells. These are activated by enzymes known as
proteases and are therefore called Protease Activated Receptors (PARs). PARs appear to be very important
'sensors' of proteases outside cells, becoming activated in response to very low concentrations of proteases. This
suggest that proteases may exert some of their biological effects through these receptors, which are now
implicated in a growing number of diseases (e.g. thrombosis, cardiovascular disorders, asthma, inflammatory
bowel disease, Crohn's disease, pancreatitis, stomach and colon cancer, arthritis, and there may also be a role in
wound healing). We are working towards dissecting the roles for one of these receptors (PAR2) in disease by
developing small molecules for selective binding to this receptor. We will particularly distinguish between
compounds that can activate (agonists) or deactivate (antagonists) the receptor. These experiments will involve
computer-assisted compound design, structural comparisons between small molecules with activity and those
without, and cellular studies designed to measure affinity, activation and deactivation of PAR2. The outcome will
be a series of small molecules that bind tightly to the PAR2 receptor and have a well defined function (antagonist,
agonist, partial agonist). While the above studies are in progress some peptides that are known to activate this
receptor will be examined in rodent models of human disease (airways inflammation, pancreatitis, stomach and
colon cancer, arthritis). Studies like this have been very revealing for us in the past (Nature 1999, 398, 156-160 "A
protective role for protease-activated receptors in the airways"). Then the designed and developed compounds will
also be examined for signs of therapeutic potential. The work will provide a better understanding of how this
receptor works and a clearer picture of the role of this receptor in human disease.

Research achievements (from final report):

PAR2 has been idntified and investigated on 30 epithelial and endothelial cell types, and a potent agonist has been
examined for effects on gene expression in two cell types. Structure-activity relationships for several hundred
peptidic agonists provided information used to create the first PAR2 antagonists as well as the first nonpeptidic
agonists. The structures of these compounds were determined, a model was created for their interaction with the
transmembrane region of PAR2, and mechanisms of agonismwere investigated. Preliminary in vivo studies were
also conducted to begin documenting the role of PAR2 in inflammatory diseases.

Expected future outcomes:

The research results pave the way for a new class of antiinflammatory and antiproliferative drugs to be developed.
The information gathered in this project provides new insights to the role of PAR2 in proliferative and
inflammatory processes and disorders and new probes for analysing this novel type of GPCR.

Name of contact:      David Fairlie
Email of contact:     d.fairlie@imb.uq.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      301239                                            Start Year:       2004
CIA Name:      Prof Gwendolen A Jull                             End Year:         2005
Main RFCD:     Therapies and Therapeutic Technology              Total funding:    $108,789.00
Admin Inst:    University of Queensland                          Grant Type:       Development Grant


Title of research award: Cranio-cervical dynamometry in the rehabilitation of neck pain

Lay Description (from application):

Research has demonstrated that exercising particular neck muscles in a specific manner is effective in reducing
painful neck symptoms. A device has been developed to quantify the performance of specific neck muscles,
permitting more precise rehabilitative exercise, tailored to an individual’s abilities and needs. The effectiveness of
this device in the rehabilitation of chronic neck pain will be tested in a clinical trial against other commonly used
forms of neck exercise.

Research achievements (from final report):

Neck pain is a common and costly problem in the community. Training of neck muscles has been shown to be
effective in reducing neck pain and disability. This study compared a new tecnology for rehabilitating the muscles
of the neck to other commonly used methods in clinical practice. Results have shown the new technology was as
effective as other commonly used methods of rehabilitation in reducing painful symptoms, as well as
demonstrating some superior results in neck muscle performance gains compared to the other methods. The new
technology was also adaptable for use in home setting, which has increased its commercial potential.

Expected future outcomes:

The Neckmetrix technology has undergone further development to refine the commercial attractiveness of the
device. Negotiations with potential licencees are in progress. Further clinical trials are planned.

Name of contact:       Dr Shaun O'leary
Email of contact:      s.oleary@uq.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      276415                                            Start Year:      2004
CIA Name:      A/Pr Edith M Gardiner                             End Year:        2006
Main RFCD:     Endocrinology                                     Total funding:   $489,750.00
Admin Inst:    University of Queensland                          Grant Type:      Standard Project Grant


Title of research award: Anabolic Bone Gene Pathways

Lay Description (from application):

Osteoporosis is a major health burden resulting from bone fractures in older men and women due to progressive
loss of bone and weakening of the skeleton. Although there are currently therapies to reduce bone loss, no current
treatment effectively reconstructs lost bone. In this project, which is designed to identify new genes that may in
the future be targeted by drugs to reverse osteoporosis, we have identified specific sets of genes that appear to
work together to increase bone formation. This proposal is aimed at characterising these genes and the ways in
which they work to determine whether they may be good targets for new osteoporosis treatments. We will
examine the patterns of these genes in bone. We will also use cell cultures in which bone forming cells develop
and function, to determine when the genes are expressed and how they function. We will test the ability of the
candidate genes to cause an increase in the amount of bone forming activity in these cell cultures. An increase in
bone formation may be caused by an increase in the number bone-forming cells, an increase in the activity of the
cells, a decrease in cell death, or a combination of these changes. Each possibility will be tested. This research is
important because of the need for new osteoporosis therapies to repair weakened bones. The knowledge resulting
from this proposal has the potential to provide an important contribution to skeletal health and thus aged health
worldwide.

Research achievements (from final report):

Osteoporosis is a condition in which bones are fragile, at least in part because of a decrease in bone mass. In
osteoporosis research, the Wnt regulatory pathway is being studied because it can increase bone mass by
increasing the activity of osteoblasts, which are the bone forming cells. How the Wnt pathway stimulates
osteoblast activity is not well understood, however, and in this project we have unexpectedly discovered that
under some circumstances, Wnt pathway activation can inhibit the bone forming activity of osteoblasts. In
experiments designed to explain how this unusual observation could occur, we have demonstrated that Wnt can
alter the expression of key genes that control the development and maturation of osteoblasts. We have also
discovered a novel mechanism of interaction between the Wnt pathway and another major regulator of osteoblasts,
the vitamin D response pathway. The knowledge gained in these experiments is important because any future
osteoporosis therapies based on Wnt pathway activation must take into account the potential negative as well as
positive effects of such interventions. Better understanding of the range of consequences of Wnt activation
including the effects on the osteoblastic vitamin D response will aid in the development of effective strategies for
both Wnt and vitamin D based therapies.

Expected future outcomes:

Future studies will determine why the negative effects of Wnt activation on bone formation occur under some
circumstances but not others.

Name of contact:       Edith Gardiner
Email of contact:      e.gardiner2@uq.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      301137                                             Start Year:      2004
CIA Name:      Prof Jennifer L Stow                               End Year:        2006
Main RFCD:     Protein Targeting and Signal Transduction          Total funding:   $467,000.00
Admin Inst:    University of Queensland                           Grant Type:      Standard Project Grant


Title of research award: LPS-regulated SNAREs and control of cytokine secretion in macrophages

Lay Description (from application):

TNF(tumour necrosis factor alpha) is a potent proinflammatory cytokine secreted by immune activated
macrophages. TNF has essential roles in host defense, tumour killing and energy metabolism. Excessive secretion
of TNF in acute and chronic inflammatory conditions, such as septic shock, Crohn s disease, rheumatoid arthritis
and in cancer has many severe, even fatal, consequences. Improved anti-TNF therapeutics are needed for clinical
management in all of these conditions. Our studies are focused on investigating how macrophages synthesize and
secrete TNF, with the ultimate goal of characterizing the molecules and vesicles in the TNF secretory pathway.
Our recent findings show the expression of SNARE proteins, part of the vesicle docking and fusion machinery, is
regulated in concert with cytokine secretion and other trafficking changes in activated macrophages. We identified
the proteins Syntaxin4, Munc-18c and SNAP-23 as the specific t-SNARE complex that regulates TNF delivery to
the cell surface. In the proposed studies we will investigate how SNAREs are regulated during macrophage
activation by studying their gene expression and protein modifications. We have developed a single-cell assay to
measure TNF trafficking in macrophages; this allows the identification of molecules with roles in TNF secretion
and it will be used in a series of experiments to identify the specific v-SNARE proteins that partner the t-SNARE
for TNF delivery. Finally we will use live cell imaging to investigate how and where TNF is delivered to the
macrophage cell surface and membrane fractionation to examine a role for membrane microdomains in organizing
SNARE-mediated TNF secretion. Manipulation of SNAREs, using data generated by these studies, holds potential
for the development of new anti-TNF therapies.

Research achievements (from final report):

We have discovered new and unexpected cellular pathways that lead to the releae of cytokines or chemical
messengers from immune cells. These cytokines have necessary roles in inflammation and describing their
pathways for release generates a new level of understanding in this area. However the excess secretion of these
cytokines, TNF and IL-6, causes the chronic symptoms of inflammatory dieases like IBD and arthritis. Our
findngs identify, for the first time, molecules important for cytokine secretion that can potentiallly be targeted by
drugs for alternative and improved approaches to treating inflammation.

Expected future outcomes:

Our findings uncover potentially drug targets and strategies for blocking TNF secretion that could lead, in the
future, to new medicines for inflammatory disease.

Name of contact:       Jennifer Stow
Email of contact:      j.stow@imb.uq.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      301178                                            Start Year:      2004
CIA Name:      Prof David P Fairlie                              End Year:        2006
Main RFCD:     Pharmacology not elsewhere classified             Total funding:   $450,000.00
Admin Inst:    University of Queensland                          Grant Type:      Standard Project Grant


Title of research award: C3/C5 Covertase inhibitors as a new class of antiinflammatory drugs

Lay Description (from application):

Many serious inflammatory diseases, such as arthritis, septic shock, lung shock, heart disease, atherosclerosis,
multiple sclerosis, are poorly controlled with currently available drugs. There is a great deal of evidence that
naturally occuring "Complement" proteins in human blood are involved in exacerbating these and many other
human diseases, yet there are no good drugs available to counteract their effects. Three complement proteins
known as C3a, C5a and MAC (membrane attack complex) are thought to be particularly pivotal components of
the complement system synthesized by the human body early in the development of inflammatory and immune
diseases. New compounds that could block the formation of human C3a, C5a and MAC are expected : (a) To lead
us to a better understanding of how these proteins act on immune cells and of their respective roles in the immune
response to infection and injury, and (b) To enable the rapid development of an entirely new class of drugs for
treating autoimmune and inflammatory diseases. No Complement-based drugs are yet available in man. In other
NHMRC funded work we have developed compounds ("antagonists") that selectively block the actions of human
C3a or C5a, and shown that they are effective antiinflammatory agents in rat models of a number of inflammatory
diseases. In this project we will design and develop small molecules that block the enzymes ("C3/C5 convertases")
that make C3a, C5a and other complement proteins including MAC. We expect that such inhibitors will be even
more effective antinflammatory drugs because they will block formation of multiple complement proteins that
each have proinflammatory activity. We will demonstrate selective effects of the new compounds on components
of complement, and test them in rat models of inflammatory diseases. We expect C3/C5 convertase inhibitors to
be a completely new type of anti-inflammatory drug, treating disease processes rather than symptoms like current
drugs.

Research achievements (from final report):

In this project we have studied some very important enzymes from human blood (the serine proteases known as
Complement factor B, C2, and C3 convertase) that are known to contribute to both immune defence and
inflammatory diseases. We have : (a) profiled their biochemical functions, (b) identified conditions that allowed
the first observation of catalytically active factor B and C2, (c) successfully created the first assay protocols for
efficient screening of inhibitors, (d) designed and developed the first potent small molecules to block the functions
of these enzymes, and (e) shown blockade of the formation of downstream products of complement activation
(namely C3a, C5a and membrane attack complex). These enzymes are not affected by other serine protease
inhibitors that we have tested. These studies are facilitating the development in our laboratories of an entirely new
class of antiinflammatory drug that intervenes directly in disease development rather than targetting symptoms of
inflammatory disease.

Expected future outcomes:

Our discovery of potent inhibitors of human complement enzymes has potential to be developed into human
pharmaceuticals with antiinflammatory properties and to be used to gain further insights to different paths of
complement activation in humans. Our focus on human enzymes, cells and inflammation in rodents is expected to
extend to more animal studies and ultimately a clinical trial.

Name of contact:      Professor David Fairlie
Email of contact:     d.fairlie@imb.uq.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      252934                                             Start Year:      2003
CIA Name:      Dr Liza-Jane Raggatt                               End Year:        2007
Main RFCD:     Cell Physiology                                    Total funding:   $254,000.00
Admin Inst:    University of Queensland                           Grant Type:      Peter Doherty Fellowship


Title of research award: The involvement of syndecan-4 and fibroblast growth factor 2 in the anabolic actions of
parathyroid hormone

Lay Description (from application):

No available Lay Description

Research achievements (from final report):

Musculoskeletal diseases are a national and international health and research priority. The work funded by this
fellowship investigated a number of important areas of bone biology. 1. There are currently very few anobolic
treatments availible to regrow fragile or damaged bones. Daily treatment with parathyroid hormone (PTH, know
by the trade name FORTEO) is one therapy availible however our current understanding of how PTH works is
limited. Syndecan-4 is a molecule regulated by PTH in bone forming cells and these studies provided knowledge
that contibutes to our understanding of how PTH works to build bone. 2. The gold standard bone substitute used in
orthopaedic surgery is allograph and autograph bone, however, they both have significant limitations. The
fabrication of artificial bone scaffolds that can be used to replace and repair injured or diseased bone are a clinical
necessity. These studies investigated the capacity of PHBV (a bacterially derived plastic) to support the growth of
bone forming cells and the potential use of this polymer in orthopaedic applications. 3. The description of
macrophages as a significant cell population on bone surfaces and their role in bone dynamics is a paradigm
changing contribution to the field of bone biology. Knowledge that there is a third population of cells involved in
regulating bone homeostsis increases our undertanding of bone and ultimately will broaden the treatment options
avalible for muscloskeletal diseases.

Expected future outcomes:

The aim of the research undertaken in this fellowship was to increase our understanding of bone formation. The
future outcome of this work will be superior therapeutic tools and treatments that will improve bone repair and
accelerate the building of new bone.

Name of contact:       Liza-Jane Raggatt
Email of contact:      l.raggatt@imb.uq.edu.au
                            NHMRC Research Achievements - SUMMARY
Grant ID:      401553                                             Start Year:      2006
CIA Name:      Dr Mark R Forwood                                  End Year:        2008
Main RFCD:     Orthopaedics                                       Total funding:   $399,750.00
Admin Inst:    University of Queensland                           Grant Type:      Standard Project Grant


Title of research award: Molecular and histopathological investigation of stress fracture healing and effects of
anti-inflammatory drugs

Lay Description (from application):

Stress fractures are debilitating injuries affecting children, adolescents and adults in sport, and army recruits. They
also occur in horse and greyhound racing, often resulting in euthanasia of the animals involved. They incur
considerable costs in medical expenses, time lost from sport and interruption to military training. But, there is
almost no information on the mechanism of healing of these fractures. Non-steroidal anti-inflammatory drugs
(NSAIDs) are still the most widely used medication in management of musculoskeletal injuries, yet their effect on
healing of stress fractures is unknown. NSAIDs delay fracture healing, but until recently there has been no
standardised way of studying stress fractures. We have created, for the first time, a well-characterised, non-
invasive model of stress fractures in the forearm of rats that closely resembles the clinical situation. This provides
a novel and unique opportunity to determine the histological and molecular mechanism of stress fracture healing,
and to investigate effects of antiinflammatory/analgesic medications on this process. Rats will have an
experimental stress fracture produced in one forelimb, and its healing will be examined up to ten weeks using
microscopic investigation and analysis of the genes that are turned off or on to initiate the process. Groups of rats
will also be treated with antiinflammatory drugs such as ibuprofen, specific COX-2 inhibitors and a new class of
drugs that target early immune responses called C5a receptor antagonists. The analgesic Paracetamol will also be
investigated as an alternative to the NSAIDs described above. There is widespread use of anti-inflammatory
agents in managing stress fractures, so it is vital that their effects on stress fracture healing be examined. This
project has enormous significance for optimising approaches for clinical management of stress fractures and for
understanding the interaction of anti-inflammatory or analgesic agents in that process.

Research achievements (from final report):

1. We have provided the first detailed analysis of the biological mechanisms of healing of stress fractures. 2. We
have reported original observations on gene expression for molecules that are important to signal new bone
remodelling that is targeted towards healing the stress fracture. These data were accepted for oral presentation at
the Annual Meeting of the American Society of Bone and Mineral Research, the largest international meeting in
the field at which only 30% submissions achieve orals. This work attracted a New Investigator Award for Ms Lisa
Kidd who presented the data (these data accepted for publication in the journal Bone). 3. We demonstrated that
non-steroidal anti inflammatory drugs retard the rate of healing of stress fractures, with distinct effects on bone
formation or resorption depending on the specificity of their action. 4. We demonstrated that osteoporosis drugs
like bisphosphonates retard the early resorption phase of remodelling of stress fracture healing. These outcomes
provide unique insights in to the mechanisms of healing of stress fractures that may inform approaches to surgical
intervention in the case of non-healing stress fractures. They also highlight the potential for altered healing when
common anti inflammatory drugs are used, or stress fractures occur in the context of anti-resorption therapy.

Expected future outcomes:

Based on these data, we are investigating an approach to re-activate bone remodelling at sights where stress
fracture healing is incomplete

Name of contact:       Mark Forwood
Email of contact:      m.forwood@griffith.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      401598                                        Start Year:          2006
CIA Name:      Prof Paul W Hodges                            End Year:            2008
Main RFCD:     Rehabilitation and Therapy: Occupational and Physical              Total funding: $291,250.00
Admin Inst:    University of Queensland                      Grant Type:          Standard Project Grant


Title of research award: Pain and trunk muscle control: Effects, mechanisms and consequences

Lay Description (from application):

Twenty-one percent of Australians report long-term back problems. This makes back pain the most common
chronic pain in Australia and most prevalent disorder among the National Health Priority Areas. For the majority
with recurrent and chronic problems, the cause is unknown but changes in control of the spine are thought to be
important. It is well accepted that pain and injury to the low back affect the way that we control the back muscles
and this leads to changes in spinal function. However, despite considerable investigation of this problem, there is a
distinct lack of consensus for how the control of movement is changed during pain, why it changes, and whether
these changes lead to further problems in the long term. The objective of this series of studies is to determine how
the adaptation to pain changes the control of the spine. We will use a range of techniques that include tests of the
strategies used by the brain to control the spine and mathematical models to estimate the effect that these changes
have on the spine when people are given back pain by injecting sterile salty water into the back muscles. These
studies will be backed up by measures of mechanical properties of the spine and by comparison to people with
clinical pain. This combination of methods has not been used previously and is likely to help resolve the problem
of how muscle control is chaged in back pain. We will also test a range of hypotheses regarding how pain has its
effect on muscle activity. A final series of studies aims to determine whether the failure of these changes in
muscle control to resolve after an epiosde of back pain leads to increased recurrence of pain in the long-term. The
importance of this project is highlighted by the significance of back pain as a major health issue, the lack of
consensus regarding the effect and mechanisms of pain on trunk muscle control (despite extensive investigation),
and the potential for the findings to guide rehabilitation and management.

Research achievements (from final report):

The results of this program of research have redefined the understanding of how movement changes in people
with back pain. In recent years there has been an explosion of exercise interventions that aim to make the spine
more stable. Terms like "core stability" and "stabilisation exercise" are commonly used to describe exercise for
back pain in gyms and the media. This exercise approach is based on the assumption that the spine is unstable. We
proposed a different hypothesis, that many people with back pain use strategies to increase spine stability to
prevent further pain and injury, and that these "protective" strategies may be problematic in the long-term. This
series of studies developed novel methods to study mechanical spine properties and control of trunk muscles in
healthy individuals, and people with clinical or experimentally induced back pain. Results showed that rather than
being unstable, people with back pain have increased stiffness and this is associated with increased muscle activity
consistent with protection of the spine. Other studies provide understanding of the underlying mechanisms for
these changes and the potential negative consequences. The studies also provide the first evidence that dynamic
control is compromised in back pain, which is a new target for intervention. In summary this research challenges
the assumptions of a very common clinical intervention and provides new directions for future developments for
management of people with back pain, which is one of the most common and costly health conditions in Australia.

Expected future outcomes:
This work has provided the basis for a new program or research that aims to investigate the association between
spine control and recurrence or persistence of back pain, and the association with psychological and social
parameters. The research also opens avenues for development and refinement of rehabilitation strategies.

Name of contact:      Paul Hodges
Email of contact:     p.hodges@uq.edu.au
                            NHMRC Research Achievements - SUMMARY
University of Sydney

Grant ID:      107203                                        Start Year:           2000
CIA Name:      Prof Kathryn Refshauge                        End Year:             2002
Main RFCD:     Rehabilitation and Therapy: Occupational and Physical               Total funding: $234,601.66
Admin Inst:    University of Sydney                          Grant Type:           Standard Project Grant


Title of research award: Exercise or advice for low back pain?

Lay Description (from application):

Low back pain (LBP) is highly prevalent and enormously expensive to society: total payments made by
Workcover for injuries to the low back were in excess of $530 million in NSW in 1996. Chronic LBP (pain lasting
more than 3 months) accounts for up to 90% of these costs. Prevention of a large part of this costly problem could
be achieved by effective treatment at the earlier sub-acute phase of LBP (6 weeks to 3 months duration). Exercise
and advice are two widely-used treatments for sub-acute LBP, yet remarkably, their efficacy is unknown. For the
first time, this study will rigorously evaluate the effectiveness of both a supervised exercise program and advice to
return to normal activity for sub-acute LBP. When this study is completed, Australian practitioners will be able to
adopt evidence based practice when managing sub-acute LBP. In addition, the study's results will enable
practitioners to select the most effective treatment for each individual patient. The results of this study should lead
to a large reduction in the incidence of chronic LBP, therefore the results should lead to significant savings in
terms of social and economic costs.

Research achievements (from final report):

N/A

Expected future outcomes:

We will complete analysis of three month and 12 month outcome data within the next three months. We will also
analyse the data about predictors of prognosis for subacute low back pain, determining who responds best to
exercise or advice. Our findings to date provide evidence that exercise and advice are effective treatments to
decrease pain and disability for subacute low back pain. However, there are many different types of exercise
programs, and we investigated only one form of exercise. We will continue this research program by investigating
the most effective types of exercise and the most successful methods of implementation. In addition, we are
currently extending the findings of the systematic review by conducting a rigorous study to determine accurately
the prognosis of acute low back pain. We will also determine the accuracy of diagnosis of spinal pathology from
questions asked in the history. The ultimate benefits of our research progam are that patients with low back pain
will be treated more effectively, and more accurate predictions of prognosis can be made.

Name of contact:       Prof Kathryn Refshauge
Email of contact:
                            NHMRC Research Achievements - SUMMARY

Grant ID:        153712                                           Start Year:       2001
CIA Name: Prof Stephen W MacMahon                                 End Year:         2003
Main RFCD: Orthopaedics                                           Total funding: $362,500.00
Admin Inst: University of Sydney                                  Grant Type: Standard Project Grant
Title of research award: Randomised trial of ibuprofen for the prevention of ectopic bone-related pain and
disability after hip replacement. HIPAID
Lay Description (from application):
Joint replacement is a well-established treatment for severe osteoarthritis of the hip. While most patients benefit
substantially from the procedure, many still experience some pain and disability after surgery. New evidence
suggests that one important cause of this pain and disability may be abnormal bone deposits that form in the
muscles around the hip (ectopic bone formation) during the first few months after surgery. Ectopic bone formation
is seen in about 40% of all patients with hip replacements. If the formation is extensive, all movement of the hip is
lost and revision surgery is necessary. However, even when the formation is less severe, movement at the hip can
be restricted resulting in pain and disability. There is growing evidence that treatment with a non-steroidal anti-
inflammatory drug at the time of surgery may halve the risk of ectopic bone formation. While this would be
expected to decrease the risk and severity of post-operative pain and disability, there is little evidence available
about the long-term effects of these drugs after hip replacement. For this reason, together with concerns about
possible side-effect of these drugs, orthopaedic surgeons have generally been reluctant to prescribe these drugs
routinely for the prevention of ectopic bone formation. Ibuprofen appears to be the non-steroidal anti-
inflammatory drug with the lowest risk of side effects. If it was shown to be effective in reducing the incidence of
pain and disability associated with ectopic bone formation after hip replacement, it may well be considered
worthwhile by doctors and patients alike. If such benefits were realised, this preventive strategy is likely to be a
highly cost-effective way to improve long-term outcome among the rapidly growing numbers of patients that
receive hip replacements. This study will provide reliable evidence about the short and long-term effects of
ibuprofen among 1,000 patients receiving hip replacements in Australia.

Research achievements (from final report):

Worldwide, HIPAID is the largest randomised clinical trial conducted to date investigating the risks and overall
benefits of a perioperative course of a non-steroidal anti-inflammatory drug (ibuprofen) amongst people
undergoing elective hip replacement surgery. 902 patients were randomised from more than 20 orthopaedic
surgery centres throughout Australia and New Zealand. Bleeding and adverse events were closely monitored
during the study treatment period. Benefits were assessed 6 to 12 months after surgery and included a wide range
of both well-validated patient self-reported outcomes (pain, physical function, general health status and global
assessments of treatment effectiveness) as well as objective measures of physical performance (range of hip
flexion, walking speed). Loss to followup was minimal: less than 6% for the main outcome: self-reported physical
function. HIPAID confirmed that hip replacement surgery is extremely beneficial for most patients with
osteoarthritis, resulting in greatly reduced pain and improved physical function and mobility. HIPAID also
confirmed that more than 40% of patients will develop ectopic bone after elective hip replacement surgery and
that a short perioperative course of ibuprofen (1200mg for 14 days) will significantly reduce the risk of
developing ectopic bone without significantly increasing bleeding or the rate of adverse events. However, the
periooperative anti-inflammatory treatment did not appear to markedly improve the considerable long-term
benefits already achieved by the hip replacement surgery.

Expected future outcomes:

This unique data set will be further explored to analyse how closely ectopic bone is associated to poor outcome
and if any patient characteristics or peri-operative events increase the risk of developing ectopic bone or poor
outcomes to surgery (approximately 15% of this sample did not report that their hip was 'much better' after
surgery.

Name of contact:      Dr Marlene Fransen
Email of contact:     mfransen@thegeorgeinstitute.org
                            NHMRC Research Achievements - SUMMARY

Grant ID:      211254                                        Start Year:            2002
CIA Name:      Dr Anne M Moseley                             End Year:              2003
Main RFCD:     Rehabilitation and Therapy: Occupational and Physical                Total funding: $55,000.00
Admin Inst:    University of Sydney                          Grant Type:            New Investigator


Title of research award: Randomised controlled trial of stretching for contracture after ankle fracture

Lay Description (from application):

Restricted ankle motion (contracture) commonly occurs after cast immobilisation following ankle fracture. The
prevalence of contracture could be as high as 77% immediately following cast removal. This interferes with tasks
such as walking and stair climbing, and can result in significant disability. While physiotherapists regularly treat
contracture after ankle fracture, the efficacy of specific treatment programs has not been established. This project
aims to determine the effectiveness of two commonly used stretching programs for contracture after ankle fracture
initially treated with cast immobilisation. Stretches of short and long duration will be compared to a no stretch
condition. The study will determine the effects of these interventions on ankle flexibility, ability to perform
everyday tasks (eg, walking), self-ratings of disability and pain.

Research achievements (from final report):

A common sequel of cast immobilisation for ankle fracture is loss of ankle joint range of motion. This is often
treated by a program of stretching, but it is not known how much stretch is required or if, for that matter, stretch is
effective. The aim of this study was to compare the effects of short (6 minutes) and long (30 minutes) duration
stretches with a control condition for the treatment of contracture after ankle fracture. Our multi-centre, assessor
blinded randomised controlled trial revealed that the addition of a program of passive stretches confers no benefit
over exercise alone for the treatment of plantarflexion contracture after cast immobilisation for ankle fracture.

Expected future outcomes:

Now that it has been shown that a clinical stretching protocol does not increase joint range of motion or reduce
disability in people with contracture following cast immobilisation for ankle fracture, physiotherapists can
discontinue prescription of stretching programs as part of the routine management of ankle fractures.

Name of contact:       Dr Anne Moseley
Email of contact:      amoseley@mail.usyd.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      211124                                           Start Year:       2002
CIA Name:      Prof Rebecca S Mason                             End Year:         2004
Main RFCD:     Endocrinology                                    Total funding:    $225,000.00
Admin Inst:    University of Sydney                             Grant Type:       Standard Project Grant


Title of research award: Nutrient dependent signaling in bone via calcium sensing receptors

Lay Description (from application):

Osteoporosis is a major health problem that affects as many as 10% of the Australian Community and costs the
health budget millions of dollars each year. A number of key nutritional factors including calcium and dietary
protein intake are known to be important in the development of osteoporosis. This proposal will test the
hypothesis that human bone cells express a protein which senses calcium and amino acids, the calcium-sensing
receptor, and thereby respond to nuritional signals arising from the presence of calcium ions and amino acids in
plasma. Furthermore, we propose that by promoting osteoblast proliferation, maturation and survival, the calcium
sensing receptor acts as the key molecular mechanism by which dietary calcium and protein promotes bone
formation.These studies have potential to explain relationships between bpne resorptive activity, which raises
local calcium concentrations, and bone formation activity and the coupling of bone forming and resorbing activity.
These studies have the potential to explain the positive effects of calcium and protein intake on bone mass and
may also shed light on the regulation of the coupling between osteoblastic and osteoclastic activity

Research achievements (from final report):

The studies examined whether the sensor which detects extracellular calcium concentrations and also responds to
amino acid concentrations is present and functional in human bone cells. Both the calcium sensing receptor
protein and messenger RNA were detected in bone cells. Furthermore, stimulation of bone cells with calcium or
other agents like calcium, including gadolinium and strontium stimulated bone forming cell proliferation and
turned off signals that would lead to bone resorption. Strontium is currently used in the treatment of osteoporosis,
though its molecular and cellular mechansims of action are unknown. Further studies indicated that bone cells
responded to specific calcium-receptor active agents, though the nature of the response was not always
stimulatory. These studies provide evidence to support the proposal that the calcium sensing receptor is present
and functional in bone cells, although with unusual characteristics. The data also show that calcium in this system
acts like a bone coupling agent and strontium, a newly released bone active agent, may act via a similar sensing
mechanism, though strontium is 10-fold more potent in bone cells than in other cell types so far described.

Expected future outcomes:

These results are important, because they provide an explanation for the selective anabolic action of strontium in
bone. Further functional effects, not yet tested for may also be present. They also identify the bone calcium-
sensing receptor as a therapeutic target for the design of even more potent and specific agents which could have a
positive effect on bone mass.

Name of contact:      R S Mason
Email of contact:     rebeccam@physiol.usyd.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:       211266                                            Start Year:         2002
CIA Name: Dr James Melrose                                        End Year:           2004
Main RFCD: Orthopaedics                                           Total funding: $330,000.00
Admin Inst: University of Sydney                                  Grant Type: Standard Project Grant
Title of research award: Investigations on the regulation of intervertebral disc cell matrix metalloproteinases.
Lay Description (from application):
Degeneration of the intervertebral disc is a painful disabling condition with major socioeconomic consequences.
Medical problems associated with disc degeneration and back-pain, of sufficient severity to warrant consultation
with a physician, are experienced by 90% of the population some time during their lives. In man, back pain
increases in incidence in the third and fourth decades of life, peaks in the fifties and declines thereafter. Changes
in population demographics indicate this problem will increase in severity over the next few decades. American
Bureau of Census data indicate that between 1990 to 2010 the number of people >45 years will increase from 82
to 124 million, the number of elderly in emerging countries will also increase between 200 to 400% in the next 30
years. In the United States, back-pain is the second most common reason that people visit a physician and medical
conditions related to back-pain account for more hospitalisations than any other musculoskeletal disorder. Despite
its high incidence, associated problems of incapacity and economic implications, costed at $100 million per
annum in Australia in 1992, and US$100 billion globally in 1999-2000 (Dorland Data Networks, PA, USA) the
causes of low back-pain are still poorly understood. Disc disease is responsible for 23-40% of all cases of low
back-pain. The management of discogenic low back-pain is currently empirical, directed either toward life-style
changes to minimise symptomatology or to surgical resection or spinal arthrodesis to restrict articulation. Based
on our recent findings and those of colleagues over the last 16 years, it is our strong conviction that it should be
possible with a better understanding of disease mechanisms and with the use of modern technologies to inhibit,
reverse or ideally prevent disc degeneration. Without such basic research there will be no scientific foundation
upon which prospective therapies may be based.

Research achievements (from final report):

Defects in the intervertebral disc are difficult to treat clinically and may be a source of intense low back pain,
furthermore overloading of a biomechanically compromised disc may exacerbate this condition and lead to
propogation of the defect to other neurological structures which may also be a source of intense pain. In dense
avascular connective tissues such as the intervertebral disc the normal healing response to a traumatic insult
leading to formation of a defect in this important weight bearing structure is to lay down a stabilising collagenous
scar tissue in the defect site. Unfortunately, such scar tissue is generally less compliant and less capable of acting
as a weight bearing structure than the native connective tissue of the disc. Replacement of scar tissue with new
functional weight bearing connective tissue is only possible if the endogenous connective tissue cells remodel the
scar tissue and replace it with new functional tissue. Intervertebral disc cells are not a particularly active metabolic
cell type thus agents have been sought which can increase their cellular metabolism to encourage them to remodel
connective tissue and reconstruct mechanically damaged regions of the disc. Such an approach has provided
encouraging results in-vitro with regard to the remodelling of major structural components of scar tissue, namely
collagen and its proteoglycans. On-going studies in animal models in which intervertebral disc defects are
reproduced surgically may provide significant insights as to how dense avascular connective tissues may be
remobilised to provide new functional weight bearing connective tissues.

Expected future outcomes:

Improvement in the recovery of trauma defects in dense avascular connective tissues such as intervertebral disc
and tendon would be expected to improve their functional status and aid in the rehabilitation of affected
individuals and the mobility of the general population.

Name of contact:       James
Email of contact:      jmelrose@med.usyd.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      211278                                             Start Year:       2002
CIA Name:      Prof Philip N Sambrook                             End Year:         2004
Main RFCD:     Geriatrics and Gerontology                         Total funding:    $340,000.00
Admin Inst:    University of Sydney                               Grant Type:       Standard Project Grant


Title of research award: Epidemiology of Osteoporosis in the Frail Elderly

Lay Description (from application):

Osteoporosis, a disease characterised by skeletal fragility, is a major public health problem. The direct costs alone
of treating osteoporotic fractures have been estimated at more than $800 million in Australia. Hip fractures are the
most costly to treat and are due to a fall or injury in over 90% of cases. The frail elderly are at particular risk of
osteoporotic fractures but little is known about risk fractures in this 'at risk' group or the effect of fracture on
quality of life. This study is examining risk factors for fractures in the frail and institutionalised older person by
asessment of quantitative bone ultrasound, falls risk, vitamin D status and other biochemical markers of bone in an
attempt to identify predictors that can be modified to reduce fractures, improve quality of life and reduce mortality
due to osteoporotic fractures.

Research achievements (from final report):

In 1999, the NHMRC funded a 3 year Project Grant to assess the role of calcaneal ultrasound combined with falls
risk factors as a screening tool in a high risk population (the frail older person) for identifying those at risk of
osteoporotic fractures. This funding was extended between 2002 and 2004. Nursing homes and hostels in northern
Sydney were randomly selected from all such institutions within the Northern Sydney Area Health Service and all
residents over the age of 65 were asked to participate. The study, which recruited 2005 subjects. Findings from the
FREE Study include a very high prevalence of vitamin D deficiency as noted above, a very high falls rate and a
high fracture incidence. We observed 181 hip fractures with a rate of 367 per 10,000 person years or 8.6 % over
median 2.4 years followup. For total fractures, we observed 402 fractures during 3240 years of follow-up with an
overall rate of 1241 per 10,000 (compared with 295 per 10,000 for community dwelling women in the Dubbo
Osteoporosis Epidemiology Study) or 16.8% after 19.4 months of follow-up. Our study identfied tools that can be
used to predict future falls and fractures.

Expected future outcomes:

Further publications will refine these tools to allow prediction of those at high risk of fracture and falls and allow
preventive measures.

Name of contact:       Philip Sambrook
Email of contact:      sambrook@med..usyd.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      211151                                             Start Year:      2001
CIA Name:      Dr Ann Louise Sharpe                               End Year:        2005
Main RFCD:     Health, Clinical and Counselling Psychology        Total funding:   $195,000.00
Admin Inst:    University of Sydney                               Grant Type:      New Investigator


Title of research award: Selective attention and fear avoidance in the maintenance and management of pain
associated with rheumatoid arthritis

Lay Description (from application):

Despite advances in the treatment of RA, the condition continues to have a chronic course for the majority of
patients. Research has established that the way in which people think about pain and illness influences their
responses to symptoms. In turn, these factors can impinge on quality of life and disability. For people with chronic
pain problems, those who are fearful of pain and concentrate on symptoms have a poorer outcome in the long-
term. In RA, striking a balance between rest and exercise is thought to be crucial. As such, ignoring the pain can
lead to overactivity and subsequent joint damage and may be as unhelpful as underactivity. This project aims to
investigate the relationship between people's fear of pain and the degree to which they attend to pain. It is
suggested that those with very high or very low levels of fear towards the pain will either over-attend or under-
attend to pain in comparison to healthy controls and patients with a moderate level of fear. Optimum levels of fear
avoidance are expected to be associated with less disability and improved joint function. These findings have
implications for the management of RA. Psychological treatments for patients with RA have been found to be
effective in reducing pain, disability and improving mood. Treatments usually focus on a combination of changing
people's attitudes and behaviours. However, whether strategies that aim to change attitudes or those targeting
behaviour are more successful or have specific treatment effects is unknown. The present project will compare a
treatment targeting behaviours associated with RA and encouraging a balanace between rest and exercise, with a
treatment targeting patient's beliefs about the illness. It is expected that the treatments will have specific effects,
which may better allow tailoring of psychological management to patient's individual needs.

Research achievements (from final report):

Background: There are over 60 trials that confirm the efficacy of broad-based cognitive-behavioural treatments
(CBT) for patients with rheumatoid arthritis. However, these treatments include a variety of cognitive and
behavioural strategies and it is unclear which treatment components are effective. Aims: The present study aimed
to compare the effectiveness of a well-established CBT program in comparison to a purely cognitive (CT) and a
purely behavioural intervention (BT). Method: One-hundred and twenty-four patients with classic rheumatoid
arthritis were approached to take part in the study and 104 volunteered (84% recruitment rate). Participants were
randomly allocated to one of four groups: CBT, CT, BT or wait-list controls (WLC). Results: Those receiving
either CT or CBT had better outcomes than BT or WLC for number of tender joints and a measure of
immunological functioning. However, there were no differences at six month follow-up between CT and CBT.
Those receiving BT only improved more than the WLC on anxiety, with comparable improvements observed for
CT. Conclusions: This study suggests that cognitive therapy demonstrates some superiority over BT and (at least
in the short-term) CBT for patients with rheumatoid arthritis.

Expected future outcomes:

We have data on hypervigilance and its relationship with baseline disability and treatment-related changes. These
data will have importance in terms of whether hypervigilance is seen as a factor that contributes to maintaining
disability in patients with RA. Moreover, it will allow us to understand whether changes in hypervigilance are
associated with treatment outcome.

Name of contact:       Louise Sharpe
Email of contact:      louises@psych.usyd.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      211279                                            Start Year:       2002
CIA Name:      A/Pr Lynette M March                              End Year:         2006
Main RFCD:     Orthopaedics                                      Total funding:    $360,000.00
Admin Inst:    University of Sydney                              Grant Type:       Epidemiology


Title of research award: Economic Evaluation and Health Outcomes of Arthritis and its Treatments

Lay Description (from application):

Musculoskeletal diseases are the most common single cause of chronic disability in Australia and total joint
replacement is rapidly becoming one of the most commonly performed operations. This burden of illness is likely
to increase with our ageing population and there is an urgent need to obtain data relating to the costs and outcomes
in the Australian context so that appropriate planning of health services and resources can be carried out. The
WHO (World Health Organisation) has declared 2000 to 2010 the Bone and Joint Decade, recommending that
research into musculoskeletal disorders be a priority. We have been recruiting and following a unique cohort of
osteoarthritis and rheumatoid arthritis patients, from both the public and private health sectors, who have been
carefully documenting their health outcomes, health care costs (including primary, revision and bilateral hip and
knee joint replacement surgery), out-of-pocket and indirect costs related to their arthritis. Long-term follow-up is
now essential to obtain a clear picture of the impact of living with arthritis over time and the cost-effectiveness
and predictors of good and bad outcomes of joint replacement surgery. The information derived from this study
will be useful for patients and doctors in making their decisions about treatments, as well as for health care
providers in planning of health services for arthritis sufferers. Given that the cohorts are already established, the
study is in a unique position to provide ongoing important longer-term data for relatively low cost.

Research achievements (from final report):

We have established a unique cohort of over 900 arthritis subjects (244 non-surgical and 687 surgical - including
revision and bilateral arthroplasty). A relatively high proportion of the cohort has been maintained considering the
age of the participants and the amount of commitment required from participants. This was done using regular
telephone contact, quarterly newsletters, birthday cards, certificates of appreciation and decorative magnets.
Analysis of costs and health outcomes over 9 years for the non-surgical cohort showed that disease progression in
the OA group was slow, with slight non-significant deterioration in health status measures. The health status of the
RA group deteriorated significantly over the 9 years. Out-of-pocket expenditure increased significantly for OA
subjects from $247 to $548 per 3 months, but remained relatively stable for the RA subjects, increasing from $367
to $397 for each 3 month period. Significant improvement from pre-surgery to 12 months post-surgery was
shown. The OA group then showed no deterioration in function or increase in pain over the following eight years,
despite a worsening in general health status which may be attributed to aging of the cohort. No increase was seen
in out-of-pocket expenditure over the eight year period. It appears that joint replacement sugery amongst this
cohort is showing a sustained beneficial impact in terms of costs and outcomes at 8 years post-surgery.

Expected future outcomes:

An assessment of pre-operative self-efficacy amongst the recently recruited patients has shown that higher self-
efficacy was associated with better health status & lower costs to both the respondent & health system. Self-
efficacy is amenable to change, so these preliminary cross-sectional results suggest that increasing patients' self-
efficacy may improve post-operative outcome and reduce costs.

Name of contact:       A/Prof Lyn March
Email of contact:      lynmar@med.usyd.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      300487                                             Start Year:      2004
CIA Name:      Dr Hala Zreiqat                                    End Year:        2006
Main RFCD:     Orthopaedics                                       Total funding:   $0.00
Admin Inst:    University of Sydney                               Grant Type:      Standard Project Grant

Title of research award: Mechanisms of bone formation at the device/tissue interface: Role of Biomaterial
Surface chemistry modification
Lay Description (from application):
In 1992 300,000 prosthetic devices, artificial hips and knees were implanted into patients in a global market worth
$2.1 billion. Growth in this field of medicine has been exceptional with now more than 1 million implants carried
out each year. In 1998/99, 38,512 artificial hips and knees were implanted in Australia alone, with approximately
10% of these replacing older, failed implants. Since joint replacements provide great benefits for the patient
considerable health funding is required for joint replacements. However, failure of the implants is a major concern
to the patient and financially to our health system, especially with the ever increasing life expectancy of our
population. The long-and short-term success of an implant depends on the healthy support of the surrounding
bone. This study aims to find ways of improving the attachment of healthy bone to the implant by modifying the
surface characteristics of the implant. We will modify the surface chemistry of biomaterials with divalent cations,
such as magnesium, which is known to play a critical role in bone remodelling and skeletal development. Our goal
is to improve the formation of healthy bone that will promote a rapid and permanent fixation of implant into
skeletons. This study goes further to study the factors, inside the cell, on the cell surface and secreted by the cell,
which promote this attachment. Once these factors are identified, it should be possible to alter implant surfaces in
ways to improve stability. In this proposal we will use novel bioceramic coatings and ion beam technologies. This
study will not only improve our understanding of the interactions of bone and implant but also identify ways of
improving implants to benefit the patient's quality of life and reduce costs in this important heath area

Research achievements (from final report):

This project has provided new important information on the role surface chemistry modification of commonly
used orthopaedic implants on bone remodelling. The major finding of this study is that we describe for the first
time the development of plasma sprayed novel calcium silicate materials coated onto commonly used orthopaedic
implants (titanium alloy-Ti-6Al-4V). We found that the developed coatings possess significantly improved
bonding strength, chemical stability and cellular bioactivity compared to the currently clinically used
hydroxyapatite (HAp) coating. The chemical stability of the ceramic is an important factor influencing the long-
term stability of the coating. In this study, we found that our novel ceramics when plasma-sprayed coated has a
decreased dissolution rate compared to HAp coating, indicating that our developed novel material possesses an
improved chemical stability, compared to clinically available coatings (HAp). A major finding of our research was
that our developed material is highly bioactive inducing bone cells proliferation and differentiation, compared to
plasma-sprayed HAp coating and uncoated Ti-6Al-4V. Moreover, in vivo we demonstrated that the novel coating
induce bone formation at the skeletal tissue device interface indicating its potential application as a coating for
orthopaedic implants. This project has the potential of developing new implant materials with improved osseous
integration. With the current rate of prosthetic failures in orthopaedic patients unacceptably high, and with implant
use growing at ~10% per annum, our new biocompatible coating for implants will make a timely contribution to
reducing patient morbidity, benefiting quality of life, and making significant health care savings.

Expected future outcomes:
With the current rate of prosthetic failures in orthopaedic patients unacceptably high, and with implant use
growing at ~10% per annum, our new biocompatible coating for implants will make a timely contribution to
reducing patient morbidity, benefiting quality of life, and making significant health care savings.

Name of contact:       Hala Zreiqat
Email of contact:      hzreiqat@usyd.edu.au
                            NHMRC Research Achievements - SUMMARY
Grant ID:      352391                                            Start Year:      2005
CIA Name:      A/Pr David G Little                               End Year:        2007
Main RFCD:     Orthopaedics                                      Total funding:   $325,250.00
Admin Inst:    University of Sydney                              Grant Type:      Standard Project Grant


Title of research award: Relationship of the anabolic and catabolic responses in healing a critical sized defect in
rats

Lay Description (from application):

Delayed bone healing after trauma is a large clinical problem. Figures suggest up to 60,000 fractures result in a
delay in healing in Australia per year. Bone healing can also fail to occur in other circumstances, such as after an
operation. Research effort into new approaches to solving these problems is clearly justified. We believe that in
some situations, bone healing fails due to the body's healing response, the anabolic response, being insufficient. In
some other situations, the body's bone resorbing response, the catabolic response, may be too high and prevent
healing from occurring. In normal bone healing, there is a balance between the anabolic and catabolic response. In
disordered bone healing, these responses are out of balance. Several reasonably new treatments are available
which can increase the anabolic response or decrease the catabolic response. We have preliminary results showing
that with these agents we can bring these elements into better control, and thus drive bone healing. We have
optimised an animal model where both the anabolic and catabolic responses can be controlled. In this project, we
explore the optimisation of the timing and magnitude of anabolic and catabolic responses in bone healing.

Research achievements (from final report):

This study investigated the potential for the use of existing therapeutic agents to modulate bone repair. Many
therapies for bone diseases such as osteoporosis offer avenues for pharmaceutical promotion of bone healing in
siuations where intervention is needed. The relationship of the anabolic (bone forming) and catabolic (bone
resorbing) responses is key to this objective. We have shown that treatment with bone morphogenic proteins
(BMP's) stimulates bone healing in a complete non-union bone repair model. This healing response was further
enhanced when the BMP was combined with systemic Bisphosphonate treatment, the most common anti-
resorptive treatment for osteoporosis. The healing bones treated with these agents in combiniation were not only
larger but also more resistant to applied mechanical forces. When these agents were examined alone and in
combination in a delayed union model with reduced but not absent healing capacity, the combination therapy
again surpassed all other treatment groups, producing enhanced repair rates, size of the callus produced and its
overall mechanical strength. Parathyroid hormone (PTH) was also examined as a potential enhancer of bone repair
in both normal bone healing and our delayed union model. Even though in fractures that normally heal PTH
treatment enhanced the fracture callus size and strenght, unlike BMP's this agent was unable to enhance repair
rates in the delayed union model. The outcomes of this study highlight BMP's as superior to PTH in the treatment
of delayed or non-unions following skeletal injury. We have elucidated the different mechanisms through which
these two enhancers of bone formation act in skeletal repair environments. This study has impacted highly on the
clinical treatment of dealyed or non-union fractures.

Expected future outcomes:

These outcoms have been and will continue to be applied in clinical orthopaedics to successfully treat cases of
delayed and non-unions. Although BMP's offer the most successful treatment strategies for these cases, their
application is expensive and requires surgical intervention. Our continuing research aims to unveil a non-surgical,
systemic treatment strategy for these situations.

Name of contact:       Associate Professor David Little
Email of contact:      davidl3@chw.edu.au
                           NHMRC Research Achievements - SUMMARY

Grant ID:       352562                                             Start Year:       2005
CIA Name: Dr James Melrose                                         End Year:         2007
Main RFCD: Orthopaedics                                            Total funding: $478,000.00
Admin Inst: University of Sydney                                   Grant Type: Standard Project Grant
Title of research award: Pathobiology of the small leucine rich repeat proteoglycans in cartilage, intervertebral
disc and tendon degeneration
Lay Description (from application):
Back problems (M$700), OA (M$600), muscle and tendon disorders (M$500) accounted for 60% of
musculoskeletal (MSK) health care expenditure in Australia in 1993-1994, were the second most common cause
of presentations to a general practitioner, the third leading contributor to health system expenditure (>$3 billion)
and accounted for ~300,000 hospital admissions, ~15 million medical services and over 13 million prescriptions.
Significant disability due to MSK disease were noted in ~50% of people aged 65 years. Australian census data
indicates that ageing trends will result in an increased incidence of MSK conditions as the longevity of the
Australian population rises, exerting an ever increasing burden on the healthcare budget. Extreme levels of
sporting or physical activity from traumatic loading of joints can lead to excessive loading of collagen fibres in
MSK tissues leading to their failure and loss of tissue function. Common end stages of collagen fibre breakdown
are preceded by matrix changes which may predispose MSK tissues to enzymatic and mechanical damage. One
such change is an increased degradation of a family of small leucine-rich proteoglycans (SLRPs) which modulate
the diameter, strength and assembly of collagen fibrils and bind and modify the effects of reparative growth
factors and degradative cytokines within connective tissues. Altered synthesis of SLRPs and SLRP fragments
have been identified in abnormal intervertebral disc, cartilage and tendon. Very little is known however about how
these fragments are generated within these tissues and how they affect growth factor binding or collagen fibril
formation. This deficiency will be addressed in our proposed study which will provide novel information on
mechanisms of cartilage, intervertebral disc and tendon degeneration and potential therapeutic and diagnostic
targets which may be exploited in future studies on the treatment of these musculoskeletal conditions.

Research achievements (from final report):
Musculoskeletal disorders affecting the knee and hip represent a major cause of disability and morbidity in
Western societies, exert a severe socio-economic impact on the afflicted individuals and cause a heavy burden on
healthcare resources. Disruption of collagen fibres in musculoskletal tissues through the action of collagenolytic
matrix metalloproteinases (MMPs) and mechanical forces represent a common end stage of disease. Identifying
changes in these tissues that not only precede collagen destruction, but also predispose them to disease
progression, may provide important targets for diagnosis, disease monitoring and facilitate early intervention
strategies when the likelihood of therapeutic repair is enhanced. The small leucine rich proteoglycans (SLRPs)
including biglycan, decorin, fibromodulin, lumican and keratocan, have important linking, shape determining and
matrix organising roles which are essential for the correct functioning of musculoskeletal tissues. In the present
study we demonstrated in two publications that the SLRPs were extensively fragmented in a number of
pathological human connective tissues and in an ovine model of IVD degeneration. A further manuscript which is
currently under review showed that fragmentation of fibromodulin was dissimilar to other SLRP members in that
it was more extensively C-terminally processed. Two define MMPs (MMP-13 and ADAMTS-4) could reproduce
similar fragmentation patterns for fibromodulin to that evident in pathological cartilages. A final mauscript which
we are currently writing has determined a novel cleavage site in lumican duye to the action of ADAMTS-4 . We
have also developed and validated an ovine model to determine the changes in shoulder tendons which was
published in the top clinical arthritis journal Arthrits Rheum. This model will allow us to determine therapeutic
intervention strategies to prevent further degenerative changes in the tendon and improve tendon repair.
Expected future outcomes:
Improvements in tendon repair/prevention of further degeneration. Improvements in post surgical rehabilitation
for tendon injuries. Identification/characterisation of SLRP core protein fragments may identify them as valuable
biomarkers of joint disease progression. Identification of the enzymes responsible for their generation may
uncover useful therapeutic targets.

Name of contact:      James Melrose
Email of contact:     jmelrose@med.usyd.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      352576                                        Start Year:           2005
CIA Name:      A/Pr Christopher G Maher                      End Year:             2007
Main RFCD:     Rehabilitation and Therapy: Occupational and Physical               Total funding: $521,625.00
Admin Inst:    University of Sydney                          Grant Type:           Standard Project Grant


Title of research award: A CLINICAL TRIAL OF MANIPULATIVE THERAPY AND/OR NSAIDS FOR
SIGNIFICANT ACUTE LOW BACK PAIN

Lay Description (from application):

Acute low back pain is a disabling condition with many sufferers being unable to perform their family or work
duties due to severe pain. Treatment of acute LBP is also costly, this condition being one of the most frequent
problems managed by general practitioners. Guidelines about how to treat patients with acute low back pain have
suggested that advice and paracetamol should be the first line of treatment. In patients with insufficient pain relief
two of the most frequently used additional treatments are anti-inflammatory medication and manipulative
physiotherapy. However, to date it is not known whether the addition of one or both of these treatments results in
faster recovery for the patient. Our clinical trial will clarify whether the addition of (i) anti-inflammatory
medication and/or (ii) manipulative physiotherapy, to advice and paracetamol given by the doctor results in a
faster recovery for the patient with acute low back pain. This results of this study will make it possible for general
practitioners to manage acute low back pain in an evidence-based way.

Research achievements (from final report):

The study revealed the importance of simple treatments delivered well; in this case provision of simple analgesics
and advice as the first line of care for patients with recent onset back pain. The trial showed that adding spinal
manipulation and/or non-steroidal anti-inflammatory drug (NSAID) therapy to the first line of care does not
confer any advantage. The consequences of application of the results of this study to clinical practice will be
profound - avoiding the serious complications of NSAIDs therapy, the costs of both treatments and the
inconvenience of attending for spinal manipulation.

Expected future outcomes:

The results of the trial will be incorporated into updates of clinical practice guidelines for low back pain

Name of contact:       Prof Chris Maher
Email of contact:      cmaher@george.org.au
                             NHMRC Research Achievements - SUMMARY

Grant ID:       211226                                            Start Year:        2002
CIA Name: Prof Maria A Fiatarone Singh                            End Year:          2008
Main RFCD: Rehabilitation and Therapy: Occupational and Physical                     Total funding: $815,000.00
Admin Inst: University of Sydney                                  Grant Type: Clinical Trial/Large Scale
Title of research award: Hip Fracture Intervention Trial (HIPFIT)
Lay Description (from application):
Hip fracture secondary to falling in the elderly represents a large and rising health care problem in Australia. At
least 12,000 such hip fractures occur in the elderly in Australia each year and this number is expected to increase
substantially over the next several decades. Long term disability, nursing home placement, reduced quality of life,
and excess mortality are known sequelae of hip fracture despite successful surgical repair. Factors have been
previous identified in epidemiological research which predict poor recovery of function and the most prominent of
these are advanced age, pre-exiting mental or functional impairment, malnutrition, depression, poor social support
networks, and poor gait, balance and muscle function. Current treatment paradigms for hip fracture do not
uniformly screen for or appropriately address potentially reversible factors such as poor nutrition, neuromuscular
dysfunction, depression, strength of social supports, or risk factors for recurrent injurious falls. It is unlikely that a
unidimensional treatment will ever optimize long term functional independence in such a multifactorial syndrome.
Therefore, we propose to apply a multifaceted targeted experimental treatment package (HIPFIT) to elderly
patients admitted to hospital for repair of a fractured hip secondary to a fall. HIPFIT would begin in hospital and
continue throughout the 12 months of follow up, using individualized treatment strategies based on periodic
reassessments in these vital domains over time. The goal of the study is to reduce the number of patients requiring
nursing home care at the end of 12 months, as well as to improve independence in a range of activities of daily
living among experimental subjects. This would have significance not only in terms of large economic savings for
the health care system but reduced personal suffering and dependency on the part of the affected individuals.

Research achievements (from final report):

Between February 2003 & April 2007 we identified 1748 individuals (60% women) admitted to RPA Hospital
with potential hip fractures (median age 80 y). A total of 262 patients were found eligible for the study and
approached for their consent which was obtained from 124 patients (47% of eligible). Three assessments were
completed per participant: a total of 111 post hip fracture, 98 after 4 months & 87 after 12 months. The 12 months
intervention was implemented for 85% of the participants randomised to intervention. Drop-out rate was 10%,
lower than we conservatively anticipated, and death rate was also 10%. This is the first study to target all major
remediable contributions to recovery of function after hip fracture, including a multi-component intervention
directed at fall risk in the home, bone health, sarcopenia, muscle weakness, gait and balance impairment,
depression, cognitive impairment, nutritional deficiencies, low self-efficacy, low social support, polypharmacy,
and visual impairment. The robust RCT design, supervised 12 month intervention, and long-term followup of
functional status and place of residence/death over 5 years make this study completely unique internationally, and
a critical addition to clinical practice in this area. If the intervention proves successful as we complete our analyses
of primary and secondary outcomes, we will have demonstrated an approach that can be implemented directly into
existing health care infrastructure in Australia, as this study was carried out in the outpatient clinic of a hospital
using a variety of health care professionals who typically work in such a setting. However, the approach we took
to proactively identifying and aggressively treating etiological factors in hip fracture-related incidence and
recovery is not currently the standard of care in Australia or elsewhere, and translation of this approach to the
community will require substantive and vitally-needed educational and implementation strategies.

Expected future outcomes:

Training of health care professionals to implement this intervention in health care settings throughout Australia
and internationally. Development of multi-medial training materials to allow translational research and
dissemination into community settings.

Name of contact:       Maria A. Fiatarone Singh
Email of contact:      m.singh@usyd.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:       402462                                             Start Year:      2006
CIA Name: Prof Markus J Seibel                                     End Year:        2008
Main RFCD: Endocrinology                                           Total funding: $455,250.00
Admin Inst: University of Sydney                                   Grant Type: Standard Project Grant
Title of research award: Glucocorticoid effects on bone: the role of the osteoblast
Lay Description (from application):
Glucocorticoids (usually referred to as "cortisone") are used as therapeutic agents in almost all fields of medicine,
where they have been proven to be of great benefit to countless patients suffering from diseases such as
rheumatoid arthritis, asthma, inflammatory bowel disease and malignancies. Glucocorticoids are also of live
saving benefit to patients who have undergone organ transplantation. It is, however, well known that
glucocorticoids may also exert deleterious effects on bone, muscle, cartilage and skin, causing osteoporosis,
muscle wasting and skin damage. As a matter of fact, cortisone-induced muscle and bone disease is one of the
most frequent and serious side effects associated with glucocorticoid treatment, and substantially affects quality of
life and co-morbidity in many patients. In the present project, we aim to develop new strategies for the
understanding and prevention of costisone-induced bone disease. The first step is to investigate the mechanisms of
actions of glucocorticoids in bone. To this aim, we have generated a model in which a cortisone- inactivating
enzyme is produced in excess in the bone forming cells ("osteoblasts"). Previous studies have shown that these
cells are protected against the effects on cortisone, while other cells not producing this enzyme remained
vulnerable. We now intend to use this model to study the mechanisms of glucocorticoid action on bone and
muscle under normal and diseased conditions (e.g. in a model of glucocorticoid excess and in a model of
rheumatoid arthritis). We also intend to study how internal glucocorticoids affect the development of bone
forming cells. Our long-term aim is to uncover new ways to target drug action to the desired tissues and cells,
while protecting other tissues and cells from deleterious side effects.

Research achievements (from final report):
Our research has resulted in a novel paradigm about the role of glucocorticoids (GC; commonly referred to as
"cortisone") in the skeleton. We discovered that endogenous (i.e. internal, low level) GC control, the fate of
immature precursor cells and the development of the cranial skeleton in mice. These effects are mediated through
specific signalling molecules secreted by the cells that form bone (the osteoblasts). We further discovered that the
interaction between endogenous GC and osteoblasts plays an important role in autoimmune arthritis. Using a well
established mouse model of arthritis (K/BxN serum-induced arthritis) we found the inflammatory response was
significantly blunted in animals in which GC action on and in the osteoblast was blocked. As a result, the bones of
these latter mice were protected, while animals with intact osteoblastic GC signalling showed sever arthritis and
bone loss. These exciting and unexpected findings suggest that osteoblasts are able to modulate the immune-
mediated inflammatory response of the joint via a GC-dependent pathway. Finally, we discovered that the effects
of exogenous (i.e. external, high level) GC on energy metabolism are mediated, at leats in part, through the
skeleton and here again, the osteoblast. Using a genetically modified mouse model, in which GC are inactivated in
osteoblasts only, we demonstrated that animals with intact GC signalling gained significantly in total and site
specific fat mass, whereas mice with osteoblast-targeted disruption of GC-signalling did not. These results show
that the osteoblast plays a role in the regulation of energy metabolism. In summary, our research has revealed
hitherto unknown and exciting functions of GC, bone and its cells that affect not only bone health and
development, but also point to a central role of the osteoblast in mediating auto-immune inflammation and GC-
induced effects on bone energy metabolism.

Expected future outcomes:
Our future research will establish the mechanisms that govern GC action in osteoblasts, and how this interaction
determines how osteoblasts comntrol mesenchymal progenitor lineage commitment, immune-mediated
inflammatory responses, and effects of GC on bone, fat and energy metabolism.

Name of contact:      Markus Seibel
Email of contact:     mjs@med.usyd.edu.au
                           NHMRC Research Achievements - SUMMARY

Grant ID:      402626                                           Start Year:      2006
CIA Name:      A/Pr Christopher B Little                        End Year:        2008
Main RFCD:     Orthopaedics                                     Total funding:   $460,950.00
Admin Inst:    University of Sydney                             Grant Type:      Standard Project Grant


Title of research award: Proteoglycan metabolism in tendon degeneration

Lay Description (from application):

Rotator cuff (RC) tendon disease is a huge burden on the healthcare system in Australia and a major cause of
morbidity in our aging population. Disorders of the RC are the most common cause of shoulder pain, which
accounts for 1.2% of all visits to general practitioners. The prevalence of RC pathology increases with age to
reach 30-50% by the seventh decade of life and a staggering 70-80% by the ninth. While most cases are treated
conservatively, there are over 12,000 RC repair surgeries performed annually in Australia, with patients being
committed to a prolonged convalescence. There are no drug therapies to specifically treat RC or other tendon
injuries and many surgical repairs fail within 12 months. The limited treatment options for RC and other tendon
disorders stems from a lack of knowledge of the molecular changes that precede and lead to rupture. It is
recognised that the content of sulphated sugars or glycosaminoglycans (GAGs) on proteoglycans in tendon is the
strongest predictor of the tisues strength. Accumulation of GAG is a well-recognised feature of torn tendons in
man. The changes in proteoglycan synthesis and breakdown that precede and lead to tendon rupture have not been
defined. We have developed a new model of shoulder tendon injury in sheep that induces regional degeneration
mimicking that seen in human RC disorders. We have found changes in expression of specific proteoglycans and
their degradative enzymes in early tendon disease. The current project will use this model in combination with a
novel culture system and recently developed genetically modified mice to determine for the first time the changes
that occur over time in proteoglycan metabolism that are responsible for tendon degeneration that leads to rupture.
Successful completion of these studies will identify biomarkers to monitor disease progression and a platform for
the development of new therapeutic strategies to treat this debilitating disorder.

Research achievements (from final report):

We developed a new model of tendon injury and degeneration to investigate the cell and molecular mechanisms of
disease. These studies showed that components (proteoglycans) that are normally found in healthy cartilage in
joints accumulate in diseased tendons. This occurs through an increase in synthesis of these proteins as well as a
decrease in the amount of enzymes that normally break down these proteoglycans. As a result we show that the
tendons become stiffer and are thus more prone to tearing. This finding offers a new target to treat tendon disease
and our large animal model offeers the potential to test new treatments. In this regard we showed in preliminary
studies that stem cells may reduce the disease in torn tendons. This exciting result opens up a new possible
treatment for tendon injuries.

Expected future outcomes:

Development of improved diagnosis and treatment of tendon injury and degeneration

Name of contact:      A/Prof Christopher Little
Email of contact:     cblittle@med.usyd.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      402714                                            Start Year:      2006
CIA Name:      A/Pr David G Little                               End Year:        2008
Main RFCD:     Orthopaedics                                      Total funding:   $0.00
Admin Inst:    University of Sydney                              Grant Type:      Standard Project Grant


Title of research award: Role of the Osteoclast in Endochondral Fracture Repair

Lay Description (from application):

Failure of bone healing leads to significant pain and disability, such that augmentation of fracture repair is a
dynamic and important field of study. A full understanding of bone repair is necessary before we can hope to
introduce successful therapies. We theorise that by stimulating bone forming cells and inhibiting bone resorbing
cells we may be able to provide optimal results. Bone resorbing cells, or osteoclasts, have long been considered
essential to the initial stages of bone repair (endochondral ossification) during which the early soft cartilaginous
callus is replaced by hard mineralised callus. Our preliminary studies lead us to believe that endochondral
ossification can indeed proceed without osteoclast activity. If we can safely eliminate osteoclast function early in
the early stages of fracture repair, a number of therapeutic options open up for the augmentation of bone healing.
The return of osteoclast function is necessary in the long term, so our strategy will also need to take this into
account. This study will establish which systems are pivotal in endochondral ossification and therefore which
interventions we should explore.

Research achievements (from final report):

This study examined the role of the bone resorbing cell known as the osteoclast during the process of fractrue
repair. When a fracture heals it forms a soft cartilage callus which is then mineralised and replaced by a hard bony
callus. It is this process of replacing cartilage with bone that was the focus of this study. The osteoclast has a
pivotal role in bone tissue removal however has been considered necessary for cartilage tissue removal also. The
current work has shown in great detail that osteoclastic resorption is in fact not necessary to cartilage tissue
removal during bone repair. Instead we have shown that a group of enzymesknown as matrix metalloproteinases
(MMP's) are essential to proper cartilage tissue removal and hence bone repair. A number of cell types secrete
these enzymes including vascular endothelial cells, cells that line invading blood vessels. The outcomes from this
study carry high significance to the clinical management of osteoporosis. A number of therapeutic agents used to
treat this highly common disease target osteoclast acitivity. Hence concerns have existed about the potential of
these agents to interfere with bone repair. Our work suggests these agents will not impair bone healing due to the
elimination of osteoclastic cells from the process.

Expected future outcomes:

This group os studies will aide clinicians in decisions regarding the treatment of osteoporotic patients who sutain
or present with fractures. We will continue to work on a new line of investigation into discreet cellular processes
to provide supporting confirmation of the work we have completed in bone reapir models.

Name of contact:       David Little
Email of contact:      davidl3@chw.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      457245                                            Start Year:      2006
CIA Name:      A/Pr David G Little                               End Year:        2008
Main RFCD:     Orthopaedics                                      Total funding:   $298,000.00
Admin Inst:    University of Sydney                              Grant Type:      Standard Project Grant


Title of research award: The role of muscle cells in bone repair

Lay Description (from application):

Failure of bone healing leads to significant pain and disability, such that augmentation of fracture repair is a
dynamic and important field of study. A full understanding of bone repair is necessary before we can hope to
introduce novel successful therapies. We believe that a improved understanding of the origins of the cells involved
with bone healing may lead to new surgical, drug and cell-based therapies for the treatment of recalcitrant bone
repair. Stem cells originating from the bone marrow and periosteum are known to differentiate into mature bone
cells and produce bone. However, these tissues are damaged or have poor access to the site of bone injury in many
severe open fractures. In these cases, bone repair often initiates in a region adjacent to an opposing muscle. This
has led us to speculate that cells from the muscle may directly contribute to bone repair. Published studies, which
have be confirmed by our group, have demonstrated the strong potential for muscle-derived progenitor cells
(satellite cells) to become bone-like in response to stimuli such as bone morphogenic proteins. To put bone-
forming potential of muscle cells in perspective, we plan to expand on these studies and compare mouse satellite
cells with mouse bone marrow stem cells. In addition, we plan to use a transgenic mouse whose muscle cells
become permanently genetically transformed to stain blue. This mouse will allow us to assess the fate of muscle
cells and their contribution to bone formation in ectopic bone formation and fracture repair models. This study
will explore on the most basic level the cellular contribution of muscle to bone repair. The results of this research
project will significantly influence our therapeutic directions for improving fracture repair in the future.

Research achievements (from final report):

The goal of our research is to understand the different cell types that can contribute to bone repair. Delayed bone
union and non-union are significant complications associated with open fractures and most current interventions
do not target specific cell types. We speculated that progenitor cells from the muscle may be able to contribute to
orthopaedic repair. We used cell culture models to show that muscle progenitors are particuarly sensitive to
osteogenic stimulation in the form of Bone Morphogenetic Proteins (BMPs). BMPs are used as an adjunctive
treatment during open fractures surgery. Mechanistically, we identified an association between expression of BMP
Receptor-1A (BMPR1A) and the sensitivity of progenitor cells. This receptor may be a new potential target for
therapies aimed at mobilizing progenitor cells for orthopaedic repair. Next, we performed surgical experiments
using a special strain of genetically modified mice. In this line, muscle progenitor are permanently labelled with a
reporter gene and can be identified by histological staining. Using open fracture and traumatic ectopic bone
formation models we have proven that muscle cells actively contribute to bone formation. This is the first study of
its kind to demonstrate that this can occur in a significant manner in vivo. These studies will have the potential to
influence orthpaedic surgical practice and suggest that improved muscle access may provide additional benefits
beyond vascularity. These finding also indicate that muscle progenitors may be an important target for future cell-
based therapies for orthopaedic healing.

Expected future outcomes:

We have achieved all of the key aims of the project. We have generated new aims based upon testing the
functional importance of muscle progenitors in orthopaedic repair, and developing new therapeutic strategies for
mobilizing muscle progenitors. These will be the focus of ongoing future studies.

Name of contact:      Dr Aaron Schindeler
Email of contact:     AaronS@chw.edu.au
                            NHMRC Research Achievements - SUMMARY
University of Tasmania

Grant ID:      302203                                            Start Year:      2004
CIA Name:      Prof Graeme Jones                                 End Year:        2005
Main RFCD:     Paediatrics                                       Total funding:   $143,000.00
Admin Inst:    University of Tasmania                            Grant Type:      Standard Project Grant


Title of research award: A Longitudinal Study of Bone Development in Children

Lay Description (from application):

Osteoporosis is a major public health problem resulting in 50-75,000 fractures each year in Australia costing the
community about 800 million dollars per annum. Bone strength is a risk factor for fractures in both childhood and
in later life. Relatively little is known about bone development with the exception of calcium intake and physical
activity. This study will follow 500 children from birth in 1988 to 2004 with the aim of understanding the
contribution of lifestyle factors to bone development in this time period.

Research achievements (from final report):

This study followed 415 children from birth to age 16 years observing the development of healthy bones in
children. At age 8, we found that breastfeeding, smoking during pregnancy, diet during pregnancy, birthweight,
physical activity, sun exposure, asthma medication and fruit and vegetables were all associated with bone mass.
By age 16, smoking during pregnancy was no longer associated but both breastfeeding and birthweight were
suggesting an effect on peak bone mass. Diet is still being analysed. Vitamin D deficiency was common (40%)
and was associated with bone mass. Fractures were common in these children (179/415) and were predicted by
bone mass (heel ultrasound and DXA), breastfeeding, asthma medication and physical fitness at age 8. Bone
density also tracks from age 8 to age 16. This study has provided novel data on the role of lifestyle factors in bone
development in children which should lead to the development of programs to prevent fractures in both younger
and later life.

Expected future outcomes:

This work is likely to lead to prgrams which increase peak bone mass and decrease fracture risk in both early and
later life

Name of contact:       Graeme Jones
Email of contact:      g.jones@utas.edu.au
                           NHMRC Research Achievements - SUMMARY

Grant ID:      218200                                          Start Year:      2002
CIA Name:      Prof Graeme Jones                               End Year:        2006
Main RFCD:     Rheumatology and Arthritis                      Total funding:   $300,000.00
Admin Inst:    University of Tasmania                          Grant Type:      Practitioner Fellowship


Title of research award: Graeme Jones

Lay Description (from application):

No available Lay Description

Research achievements (from final report):

This fellowship allowed an expansion of research activities in musculoskeletal disease in Tasmania concentrating
on bone development/fracture risk in children and osteoarthritis. Many key results were achieved with 66 papers
in the 5 year time frame, 3 PhD completions, appointment to full professor, appointment as medical director of
Arthritis Australia and appointment to the editotial boards of three international journals

Expected future outcomes:

Continuation of fellowship for next 5 year will allow this work to continue

Name of contact:      Graeme Jones
Email of contact:     g.jones@utas.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      253927                                             Start Year:       2003
CIA Name:      A/Pr Alison Venn                                   End Year:         2008
Main RFCD:     Epidemiology                                       Total funding:    $2,500,000.00
Admin Inst:    University of Tasmania                             Grant Type:       Population Health Capacity
                                                                  Building Grants


Title of research award: Building Australia's capacity to study preventable causes of common diseases through
epidemiological research

Lay Description (from application):

This program of work will build Australia's capacity to study the preventable causes of common disease.
Researchers will be trained to investigate the impact of genetic, environmental and lifestyle factors on disease in
large samples of people. The diseases will include diabetes, cardiovascular disease, bone and joint conditions,
some common cancers such as skin and prostate cancer, and diseases affecting the nervous system such as
multiple sclerosis.

Research achievements (from final report):

This Capacity Building Grant in Population Health has supported research into the genetic, environmental and
behavioural determinants of chronic disease including cancer, cardiovascular disease, diabetes, osteoporosis,
osteoarthritis, multiple sclerosis and epilepsy. Specifically, over a five-year period it has provided support for the
salary and training of eleven postdoctoral fellows who have been engaged in innovative genetic and
epidemiological research. In addition, the grant supported two visiting fellows who have contributed expertise in
musculoskeletal epidemiology and biostatistics. Support of this group of researchers significantly increased the
capacity of the Menzies Research Institute to fully utilise its rich resources of research data and to train and
develop postgraduate students. The project's aim to increase capacity in population health through the training of
postdoctoral fellows and hosting visiting fellows has been met and can be measured in terms of the following
outputs: fellows were authors on 96 journal articles; 5 fellows awarded postdoctoral fellowships (4 NHMRC, 1
Cancer Council); 9 fellows involved in the supervision of postgraduate students at Menzies; 19 postgraduate
students supervised by chief and team investigators; and 6 fellows have been investigators on a total of 19 new
research grants.The fellows will continue to make a significant contribution to population health research as they
develop greater independence and leadership skills.

Expected future outcomes:

New insights into the causes and prevention of chronic disease and training of the next generation of population
health researchers.

Name of contact:       Alison Venn
Email of contact:      Alison.Venn@utas.edu.au
                            NHMRC Research Achievements - SUMMARY
University of Western Australia

Grant ID:      139137                                             Start Year:       2001
CIA Name:      Dr Jiake J Xu                                      End Year:         2003
Main RFCD:     Orthopaedics                                       Total funding:    $196,527.54
Admin Inst:    University of Western Australia                    Grant Type:       New Investigator


Title of research award: Caltrin as a calcium transport inhibitor during osteoclastic bone resorption

Lay Description (from application):

Excessive bone resorption has been observed in many common bone diseases such as osteoporosis, Paget's disease
and arthritis. These are major health problems in Australia and other developed countries. Increased activation or
formation of osteoclasts is responsible for the excessive bone resorption. Understanding the mechanisms by which
the osteoclasts exert its function and activation is an important step toward developing strategies to combat
excessive bone resorption for the treatment and prevention of osteolytic disorders. This project attempts to address
the important and fundamental issue of osteoclast function. We have identified caltrin, a known calcium transport
inhibitor, that is likely to be biologically important in osteoclast calcium homeostasis. This project intends to
investigate the role of caltrin in calcium-induced apoptosis, osteoclast bone resorption and the cellular and
molecular mechanisms underlined. It will enhance our knowledge of calcium regulation in osteoclasts and provide
information to facilitate the development of new anti-resorptive agents.

Research achievements (from final report):

Osteoporosis, or porous bone, is a disease characterized by low bone mass and structural deterioration of bone
tissue, leading to bone fragility and an increased susceptibility to fractures, especially in the hip, spine, and wrist.
It is caused by an imbalance between the cells that are constantly reabsorbing (osteoclasts) and reforming bone
(osteoblasts). We have discovered a protein expressed by osteoclasts, which has the remarkable ability to induce
intracellular calcium elevation and to stimulate the proliferation of osteoblasts. This data is very encouraging, and
has been patented through the University of Western Australia. Future study is to conduct further proof-of-concept
studies, including small scale in vivo animal trials that this protein can enhance bone formation, such a treatment
for osteoporosis.

Expected future outcomes:

N/A

Name of contact:       Jiake Xu
Email of contact:
                            NHMRC Research Achievements - SUMMARY

Grant ID:        254627                                                Start Year:     2003
CIA Name: Prof Richard Prince                                          End Year:       2004
Main RFCD: Preventive Medicine                                         Total funding: $255,500.00
Admin Inst: University of Western Australia                            Grant Type: Standard Project Grant
Title of research award:
Lay Description (from application):
Osteoporosis is a largely preventable disease yet 1 in 10 Australians have osteoporosis. Every year >64,000
osteoporotic fractures occur, which is one every 8.1 minutes and women are three times as likely to have the
disease than men. The Bone and Calcium Research Group at the University of Western Australia, is studying how
to prevent osteoporosis in elderly women. This study is called the Calcium Intake Fracture Outcome Study or
CAIFOS. During 1998, 1,500 women were recruited to study whether a daily calcium supplement for 5 years
helps to prevent fractures compared to a diet without a supplement. To do this only half of the women were given
calcium supplements and the other half were given matched placebo tablets. Each year the study participants are
reviewed and asked whether or not they have broken any bones and have other measurements to monitor their
bone health and overall health. The subjects are entering their last year of treatment and will finish the study
during 2003. At this appointment all subjects will undergo the same series of measurements that they had at the
beginning of the study to determine whether or not they have fractured any bones, improved their bone mass and
overall health during the treatment stage. The main outcome of the study is to determine whether calcium is useful
as a supplement to prevent osteoporotic fracture in elderly women. If this study finds that fewer women fractured
in the calcium treated group compared to the non treated group, given that both groups were similar to begin with,
we can say that supplementation with calcium prevents fractures. Thus, public health messages about preventing
osteoporosis will be able to direct the community to take supplements to prevent a disease that creates pain and
disability in later life. The advantage of this study is that it is studying other aspects of these women health, so we
can determine whether the calcium is safe to use and improves people's quality of life.

Research achievements (from final report):
The Calcium Intake Fracture Outcome Study (CAIFOS) was a 2 arm, randomized, double-blind, 5 year study of
calcium supplementation (1200mg/d) versus placebo in 1,500 women aged over 70 years. This has been the
largest population based randomized study of calcium supplementation in the world to determine whether calcium
supplementation in elderly women prevents fracture. Recruitment of 1500 women for the study was accomplished
between February and December 1998 from the WA electoral roll. The mean age of the population at baseline was
75.1±2.7 years. The NHMRC supported this study in 2003 (final year of data collection) and in 2004 (data
analysis phase). We now able to report the fracture and bone density outcomes of the study powered to determine
whether consumption of a calcium supplement for 5 years would reduce clinical fracture rates. The intention to
treat analysis did not indicate that calcium was effective at stopping fracture, however, in those who took calcium
tablets for five years (63%) had a 33% reduction in clinical fractures compared to those who took the placebo
tablet. We also found that there was less bone lost at the femoral neck site of the hip in those who took calcium.
This was confirmed using measurements of the whole body. We were able to determine using specialised
computed tomography of the arm that those reciveing calcium supplemntation had thicker bone which had a good
effect on bone strength. This study shows that calcium tablets are an effective and safe way of stopping bone loss
and fracture for women of this age group. This is the first study in the world to show such an important effect of
calcium supplements and we aim to publish these results in the medical literature to allow others to see the
importance of calcium supplementation as part of a public health approach to clinical fracture prevention.

Expected future outcomes:

This study shows that calcium tablets are a safe way of stopping bone loss and fracture for all women over the age
of 70 years. This important information will be used to improve the bone health of West Australian women and
will form the basis of evidence based public health messages regarding prevention of fracture using a lifestyle
approach.

Name of contact:       A/Prof Richard Prince
Email of contact:      rlprince@cyllene.uwa.edu.au
                           NHMRC Research Achievements - SUMMARY

Grant ID:      254565                                         Start Year:      2003
CIA Name: Dr David G Lloyd                                    End Year:        2005
Main RFCD: Orthopaedics                                       Total funding: $431,000.00
Admin Inst: University of Western Australia                   Grant Type: Standard Project Grant
Title of research award: A prospective study to identify the mechanical causes and methods for early detection
of knee osteoarthritis

Lay Description (from application):
Knee osteoarthritis is a great cost to society, financially and in quality of life. Anti-inflammatory drugs are
commonly used to treat the symptoms, but many people receive joint replacements to stop pain and improve
function. We need to prevent osteoarthritis, but the causes for this common disease are largely unknown. Animal
studies have shown two particular mechanical factors that cause osteoarthritis, which are seen in the walking and
running, or gait, patterns of some people. We call these "pathological gait patterns" as they impose larger-than-
normal forces on the knee's articular surfaces. We measure these knee forces with our new computer knee model
coupled with data that we measure in a gait analysis laboratory. These forces may cause knee osteoarthritis in
humans, but this is still unknown. Currently there is no simple medical test to detect the early onset of knee
osteoarthritis. The bones in the knee are one of the first structures to show osteoarthritic changes. Using our new
computerised analysis of high definition X-ray of the knee we can identify subtle differences in the knee due to
osteoarthritis. This will be compared with changes to joint assessed using MRI. Osteoarthritis develops slowly in
normal people, so to study progression of knee osteoarthritis we need a human population that has a higher risk of
developing the disease. Partial meniscectomy in the knee is a common surgery performed to improve knee
function in those who have suffered a knee meniscus injury. However, partial meniscectomy patients have a high
risk of developing knee osteoarthritis. Therefore, using partial meniscectomy patients we are investigating if
pathological gait patterns cause knee osteoarthritis, measuring the development of the disease with our new X-ray
methods. With the gait analysis methods we can also identify the movements that characterise these pathological
gait patterns so we can formulate rehabilitation programmes to help prevent knee osteoarthritis.

Research achievements (from final report):

Major objectives achieved 1. Retested 60 arthroscopic meniscectomy patients (APM) and 35 matched controls.
Baseline data at 3 months post surgery was collected from these people (100 APM patients and 50 controls) in
previous NHMRC grant (991134): Retesting included 3 dimensional gait analysis, x-rays and MRI of subject
knees, suite of questionnaires, knee muscle strength. 2. Assessed MRI status of the knee cartilage (cartilage
defects) at 4 years post surgery (1 paper submitted - Mills PM, Wang Y, Cicuttini FM & Lloyd DG. Osteoarthritis
and Cartilage 2007) 3. Assessed differences in knee motion and loading in APM patients (6 conference
proceedings, 1 paper in press, 1 papers submitted i) Sturnieks et al, Medicine and Science in Sports and Exercise,
2007, 4. Developed EMG driven model to estimate articular loading and other knee tissue loading and apply to
APM patients (4 conference proceedings, 3 papers published, 1 paper submitted - Winby CR, Lloyd DG, and Kirk
TB Journal of Biomechanics, 2007 ) 5. Developed standard atlas using fractal analysis of bone of knee
radiographs to assess knee OA status (1 conference proceedings, 1 paper in press, 1 paper submitted - Podsiadlo P,
Wolski M, and Stachowiak GW Medical Physics, 2007) 6. The framework of the study has allowed us to
continuing this work with a further NHMRC grant (334151) to assess changed in cartilage status in APM patients
7. The modelling and data analysis methods are applied to this current NHMRC grant (254565) and new NHMRC
grant (334151)

Expected future outcomes:

1. Fractal analysis of x-rays to assess knee OA status in APM patients. 2. Examine if knee loading in gait causes
development of pain, dysfunction, cartilage defects and radiographic knee OA in APM patients.

Name of contact:      David Lloyd
Email of contact:     dlloyd@cyllene.uwa.edu
                            NHMRC Research Achievements - SUMMARY

Grant ID:      254662                                            Start Year:      2003
CIA Name:      Dr Jiake J Xu                                     End Year:        2005
Main RFCD:     Orthopaedics                                      Total funding:   $225,000.00
Admin Inst:    University of Western Australia                   Grant Type:      Standard Project Grant


Title of research award: The role of V-ATPase accessory submit Ac45 in osteoclasts

Lay Description (from application):

Osteoclasts are directly related to many lytic bone disorders including osteoporosis, osteoarthritis and Paget's
diseases. Development of strategies to control the formation or activities of osteoclasts has been a major focus of
bone research. The vacuolar proton pump (V-ATPase) located on the plasma membrane of the osteoclast is
responsible for creating a low pH environment critical for bone resorption, and therefore a potential molecular
target for the discovery of novel bone antiresorptive agents useful for the treatment of lytic bone disorders. The
proposed research will give considerable insight into the role of the both V-ATPase accessory subunit Ac45 and
V-ATPase complex in osteoclasts. Understanding the molecular and cellular mechanisms by which V-ATPases
regulate osteoclast bone resorption will facilitate the development of novel and selective inhibitors for the
treatment of lytic bone disorders.

Research achievements (from final report):

Osteoclasts are the principal cells responsible for bone degradation. Overproduction and excessive activity of
osteoclasts underlines many lytic bone disorders such as osteoporosis, Paget's disease and tumor-induced bone
loss. The critical condition for the removal crystals is the use of a specific low pH in a biological
microenvironment. The vacuolar proton pump H+-adenosine triphosphatases (V-ATPases) located on the bone-
apposed plasma membrane of the osteoclast, are imperative for osteoclastic bone resorption, and thus serve as a
potential molecular target for the development of novel anti-resorptive agents. Discovery of specific osteoclast V-
ATPases subunits is an important and challenging area of bone research, might facilitate development of drugs for
the treatment of osteoporosis, Paget's disease, and various manifestations of skeletal cancer. The proposed project
addresses the fundamental role of the V-ATPase in osteoclast differentiation, acidification and bone resorption.
Understanding the molecular and cellular mechanisms by which V-ATPases subunits regulate osteoclast function
and bone resorption will facilitate the development of novel and selective inhibitors for the treatment of lytic bone
disorders.

Expected future outcomes:

Understanding the molecular and cellular mechanisms by which specific subunits of V-ATPase regulate osteoclast
function might facilitate the development of novel and selective inhibitors for the treatment of lytic bone
disorders, such as osteoporosis, Paget's disease, bone aseptic loosening and tumor-induced bone destruction.

Name of contact:       Jiake Xu
Email of contact:      jiake.xu@uwa.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      254743                                            Start Year:       2003
CIA Name:      Prof David J Wood                                 End Year:         2006
Main RFCD:     Orthopaedics                                      Total funding:    $307,400.00
Admin Inst:    University of Western Australia                   Grant Type:       Development Grant


Title of research award: Biological, functional and radiographic evaluation of autologous chondrocyte
implantation.

Lay Description (from application):

We will test the hypothesis that autologous chondrocyte implantation (ACI) and extensor realignment produces
superior clinical, biological and radiographic results when compared with conventional treatment of realignment
and debridement. We will specifically address the following aims: 1. Quantify the clinical outcome of ACI
compared to the traditionally used treatment of debridement through the use of functional evaluation in a blinded
randomised controlled clinical trial; 2. Evaluate the radiographic changes in the patellofemoral joint that occur as
a result of ACI, using high resolution magnetic resonance imaging (MRI) to quantify the regeneration of hyaline
articular cartilage; 3. Using the new technique of confocal arthroscopy, we will compare the histologic
appearances of the ACI graft and its interface with adjacent articular cartilage; 4. Evaluate patient, surgical and
explant chondrocyte characteristics in relation to functional, radiographic and biological outcomes. With respect
to the matrix-induced autologous chondrocyte implantation (MACI) technique, we wish to clarify the clinical
practice as a definitive treatment for articular cartilage defects. This will be the first randomised, controlled
clinical trial of the MACI technique compared to that used by other groups. A positive clinical outcome from this
trial will help promote the three cornerstones of this procedure – successful cell culture, efficient surgical
procedures, and complimentary postoperative rehabilitation. Furthermore, this research will: a) Enhance the
expansion of the MACI technique; b) Encourage development of endoscopic techniques of implantation using a
combination of – • Preoperative defect registration with MRI • pre-cut custom patches, implanted with •
Computer-assisted navigation techniques: c) Increase the potential to cater for a larger number of patients
requiring articular cartilage repair; d) Confirm the long-term durability of regenerated cartilage in the 4th year and
beyond; e) Add further commercial value by demonstrating MACI may prevent the onset of osteoarthritis.

Research achievements (from final report):

1. The development of matrix induced autologous chondrocyte implantation as a recognised clinical technique in
the treatment of articular cartilage defects. 2.The reduction in invasivness surgery from a wide inscision to
arthroscopic surgery. 3. A greater understanding of the histological appearances and outcomes following
autologous chondrocyte implantation. 4. Development of best practice rehabilitation protocols, in support of the
cellular and surgical advances, to ensure the best possible patient outcomes following this procedure. 5. A greater
understanding of knee joint loading (and therefore, defect graft), during the post-surgery time course with
incremental increases in patient functioning.

Expected future outcomes:

Autologous chondrocyte implantation is now an established surgical procedure for articular cartilage defects of the
knee. Biologically about 80% of tissue develops into hyaline chondrocytes and the rest into fibrous tissue. Further
outcomes should be aimed at improving the hyaline chondrocyte diifferentiation.

Name of contact:       David Wood
Email of contact:      david.wood@uwa.edu.au
                           NHMRC Research Achievements - SUMMARY

Grant ID:      303206                                         Start Year:        2004
CIA Name:      Dr Daniela Ulgiati                             End Year:          2006
Main RFCD:     Biochemistry and Cell Biology not elsewhere classified            Total funding: $466,500.00
Admin Inst:    University of Western Australia                Grant Type:        Standard Project Grant


Title of research award: Transcriptional regulation of the complement receptor 2 gene (CR2/CD21) during B
cell lineage commitment

Lay Description (from application):

The complement system is a very important pathway within the human immune system. One of the receptors
within this system is complement receptor 2 or CR2. CR2 has not only been shown to be important within the
inflammatory response and defence against microbes but is also important in normal generation of a B cell
immune response . B cells not only produce antibodies against foreign organisms but in some cases dysfunction of
the B cell can bring about autoimmunity by production of antibodies against self tissues and cells . How the CR2
gene turns on expression on different cells within the immune system is complex. The amount of receptor on the
surface of antibody producing B cells has important implications to B cell biology. As CR2 expression is turned
on at an important point within the antibody producing B cell and the levels of this receptor can influence B cell
function, understanding how this gene is regulated is important.

Research achievements (from final report):

Complement Receptor 2 (CR2) plays an important role in the generation of normal B cell immune responses. Our
work on the transcriptional control of human CR2 show that this gene is complexly regulated by the presence of
both promoter and intronic silencer elements. During the three years of this grant we have made significant
progress in further understanding the mechanisms that govern CR2 transcription. Within the functionally
important regulatory regions we have identified and characterised several novel transcription factors. We have
also analysed the transcriptional regulation of CR2 during B cell lineage development, when CR2 expression is
tightly controlled, and have successfully demonstrated that the mechanism involves both cell-specific transcription
factors but also chromatin remodelling and histone modifications. In addition, there is now very clear evidence for
CR2 playing a role in the development of Systemic Lupus Erythematosus (SLE). To explore the role of CR2 in
human SLE further, we analysed 1416 individuals from 258 Caucasian and 142 Chinese lupus simplex families
and demonstrated that polymorphisms within the CR2 gene were associated with lupus susceptibility. SNP1,
located within the 5'UTR of the CR2 gene, altered transcriptional activity suggesting a potential mechanism by
which CR2 could contribute to the development of lupus. Our findings reveal that CR2 is a likely susceptibility
gene for human lupus at 1q32.2 confirming that CR2 participates in the pathogenesis of SLE.

Expected future outcomes:

Dysregulation of CR2 expression plays a role in driving a breakdown of tolerance and promoting autoimmunity.
As the appearance of CR2 on the surface of B cells is intricately regulated at the level of transcription,
identification of factors and mechanisms that regulate this gene may result in strategies to alter CR2 expression
and modify B cell autoantibody responses.

Name of contact:      Daniela Ulgiati
Email of contact:     ulgiati@cyllene.uwa.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      303216                                         Start Year:      2004
CIA Name: Prof Steve D Wilton                                 End Year:        2006
Main RFCD: Gene Therapy                                       Total funding: $447,700.00
Admin Inst: University of Western Australia                   Grant Type: Standard Project Grant
Title of research award: Therapeutic induction of dystrophin positive "revertant" fibres in the mdx mouse

Lay Description (from application):
Revertant fibres are low-abundance, dystrophin-positive fibres found in muscle of DMD patients and animal
models. These fibres appear to have a selective advantage over dystrophin negative fibres, as they accumulate
with age. Characterisation of dystrophin mRNA has identified in-frame transcripts missing multiple exons, which
either exclude a nonsense mutation or restore the reading frame around a deletion. We have designed antisense
oligonucleotides (AOs) to bind regions flanking the exon containing the dystrophin mutation in the mdx mouse.
The AOs interfere with processing of the pre-mRNA to exclude the mutation and allow a slightly shortened
dystrophin to be synthesised. The use of AOs to modify RNA processing allows the gene to function under the
control of natural regulatory elements. We have shown that AOs can induce dystrophin expression and improve
strength in dystrophic (mdx) mouse hindlimb muscles. We aim to improve upon these results by using AOs to
block splice sites flanking consecutive exons, in order to induce dystrophin which mimics that of revertant fibres.
As most revertant transcripts are missing multiple exons, we believe that the functional capacity of AO-induced
dystrophin can be improved upon by removing multiple exons. An mdx mouse skeletal muscle cell line is used for
evaluation AOs. However, in order to determine the efficacy of the induced dystrophin in cardiac and skeletal
muscle, experiments must be performed on mice. Previous work, in vitro and in muscles of mdx mice have
validated this approach. Combinations of AOs which show promise will be delivered by a) intravascular injection
b) intraperitoneal injection in mdx mice. The efficacy of the treatment will be assessed by both continual and end
point analysis, which includes physiological, clinical, molecular and histological testing. Particular attention will
be directed to the well-being of the mice and any adverse side effects which may occur.

Research achievements (from final report):

Duchenne muscular dystrophy (DMD) is an X-linked, progressive childhood neuromuscular condition, caused by
mutations in the dystrophin gene. When dystrophin is missing from the muscle, muscle fibres are fragile and
susceptible to contraction-induced damage. Affected boys become non-ambulant by the age of 12 years and
relentless muscle wasting continues until death from cardiac or respiratory failure before the third decade.
Treatment options for DMD are limited. Becker muscular dystrophy BMD) is also caused by dystrophin
mutations, but the production of some functional protein results in variable, but generally less severe disease.
Study of the gene structure in BMD patients has lead to the development of a strategy to reduce the severity of
DMD by manipulating the processing of a DMD gene message to mimic that of a mildly affected BMD patient.
This strategy uses short synthetic nucleic acids, called antisense oligonucleotides, to block essential motifs and
exclude certain segments (exons) from the message during processing by the cellular machinery. In this way the
mutation can be by-passed. Prior to this study, we focused on designing oligonucleotides to induce efficient
removal of single exons from the dystrophin message, however, many dystrophin mutations will require the
removal of 2 or more exons to by-pass the gene lesion and produce a functional protein. In this study we
demonstrated that up to 7 exons could be removed from the dystrophin message, and that this could produce
functional protein.

Expected future outcomes:

An antisense compound (designed by the grantees) directed to exon 51 of the dystrophin message is undergoing
clinical trials in the UK. However, DMD-causing mutations may involve any of the 79 dystrophin exons. The
removal of selected exon combinations will lead to a personalised treatment for an estimated 70% of DMD
patients.

Name of contact:       Steve Wilton
Email of contact:      swilton@cyllene.uwa.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      353638                                            Start Year:      2005
CIA Name:      Prof Richard Prince                               End Year:        2006
Main RFCD:     Motor Control                                     Total funding:   $230,900.00
Admin Inst:    University of Western Australia                   Grant Type:      Standard Project Grant


Title of research award: Effects of vitamin D and calcium on bone and falls in an elderly population of
Australian women selected for their history of falling

Lay Description (from application):

Many osteoporotic fractures occur as a result of bone fragility and falls. Both falls and fractures are huge public
health problems in Australia. Falls are the leading cause of injury-related hospitalization and death in person older
than 65 years of age. During 1996 almost 36,000 people attended a hospital after a fall and 5% of these resulted in
fracturing a bone. The incidence of fall-related hospital admission increases exponentially with age, reaching 4%
per annum for men and 7% per annum for women aged 85 years and older. In the community approximately one
third of older people fall each year. Compared to men, women are three times more likely to be hospitalized or
one and half times more likely to die from a fall-related injury. Importantly women have an increased risk of
fracture and over 40% of women over the age of 50 will break a bone. Previous European and American studies
suggest that calcium replacement may improve bone strength while vitamin D may reduce falls. However, the
separation of these two effects has never been studied. We have previously studied elderly falling women who
attended the Emergency Department of large teaching hospitals in Perth and have shown that many are calcium
and vitamin D deficient. We are undertaking a short term randomized controlled trial of calcium alone or calcium
with vitamin D, to study the effects on bone strength as measured non-invasively, balance and falls in this high
risk group of subjects. We have already recruited 100 subjects and six subjects have completed their 6 months
assessment. We plan to recruit the remaining 200 subjects during the following 12 months and give all subjects
one year of treatment. At the end of this study we should be able to offer clear treatment guidelines for this high
risk group of patients.

Research achievements (from final report):

Both falls and fractures are huge public health problems in Australia. Falls are the leading cause of injury-related
hospitalization and death in person older than 65 years of age. In this one year study, we evaluated the effect of
vitamin D and calcium supplementation compared to calcium alone on falls risk in older women at high risk of
falling. The study participants were 302 community-dwelling ambulant women aged 70-90 living in Perth with
high risk of falling due to low vitamin D status and a history of falling in the previous year. Half of the
participants received vitamin D2 1000 IU per day for one year and the other half received identical placebo and all
of them received calcium 1000 mg per day. After one year, vitamin D supplementation is associated with 19%
reduction in the risk of falling. Vitamin D supplementation has no treatment benefit on falls reduction in
summer/autumn when better vitamin D status are achieved with increased incident solar radiation, but is
associated with 23% reduction of the risk of falling in winter/spring to the same level as in summer/autumn. Thus
it is proposed that in older women living in the community at high risk of falling it would be reasonable to aim to
achieve 25-hydroxy vitamin D levels of 60 nmol/L or above to prevent the risk of falling due to vitamin D
deficiency. This has resulted in a publication in a high impact journal - Achives of Internal Medicine ((Impact
factor: 7.92; in press).

Expected future outcomes:
The findings of this study are important for the development of falls prevention guidelines and strategies in
community-dewelling older women, and thus contribute to the reduction of the incidence of falls and fractures in
this population and the associated cost.

Name of contact:       A Prof Richard Prince
Email of contact:      rlprince@cyllene.uwa.edu.au
                           NHMRC Research Achievements - SUMMARY

Grant ID:      353626                                           Start Year:      2005
CIA Name:      Prof David J Wood                                End Year:        2007
Main RFCD:     Orthopaedics                                     Total funding:   $198,750.00
Admin Inst:    University of Western Australia                  Grant Type:      Standard Project Grant


Title of research award: In-vivo patellofemoral joint measurement using kinematic Radiostereometric Analysis
(RSA)

Lay Description (from application):

Complications following total knee joint replacement continue to be a major cause for revision surgery and leads
to a significant financial burden in terms of health care expenditure. Recent studies suggest that many of these
complications are associated with post-surgical pain from the patella knee cap joint, commonly termed anterior
knee pain (AKP). Post-surgery AKP may be influenced by the motion of the patella. Recent prospective,
randomised trials have compared clinical outcomes between people with TKA in which the patellar surface is
replaced (patellar resurfacing) or retained, but have been unable to accurately account for differences in patellar
movement in those people with post-surgery complications. To date, studies of patellar motion after total knee
replacement have been limited to two-dimensional analyses. This study addresses the technological limitations of
previous trials by utilising accurate techniques for directly measuring skeletal motion using kinematic
radiostereometric analysis (RSA). These data will measure patellar kinematics in three-dimensions for the first
time. This information will allow optimisation of the design of TKA and the surgical techniques required for their
implantation. Furthermore, the results will assist in the identification of surgical indications for patellar
resurfacing, and the kinematic factors associated with anterior knee pain following total knee replacement surgery.

Research achievements (from final report):

We have established a new technique in terms of evaluating the kinematics of total knee replacements and
patellas. This technique has the potential to be adapted to other prosthetic and non prosthetic joints where
kinematic problems arise through injury or degenerative disease. Essentially Kinematic RSA involves insertion of
tantalum beads (at least 3 in each fixed body) which can de identified using a calibrated cage with great accuracy.
Each segment identified can be tracked with an accuracy never before achieved. The combination of these images
can also be used to measure wear in total knee arthroplasty.

Expected future outcomes:

This technique may be applied to other joints and orthopaedic procedures to evaluate outcomes. For example,
cruciate ligament reconstruction maybe evaluated by this technique using the same computer program as for total
knee arthroplasty. Other algorithms will be required to evaluate other joints.

Name of contact:      Prof Bo Nivbrant
Email of contact:     bo.nivbrant@uwa.edu.au
                           NHMRC Research Achievements - SUMMARY

Grant ID:      353673                                           Start Year:      2005
CIA Name:      Prof Ming H Zheng                                End Year:        2007
Main RFCD:     Orthopaedics                                     Total funding:   $276,000.00
Admin Inst:    University of Western Australia                  Grant Type:      Standard Project Grant


Title of research award: The Role of P62/A170 in Pathological Bone Destruction

Lay Description (from application):

Approximately up to 30% of patients are admitted to public hospitals in Australia for reasons related to skeletal
disorders, including trauma, osteoarthritis, osteoporosis, primary and secondary bone tumours, genetic and
metabolic disorders. Abnormal bone resorption contributes to most of these diseases and conditions. Based on the
clinical evidence of P62 mutation in patients with Paget's Disease of bone and our observation of the involvement
of P62 in RANKL-induced NF-Kb signaling, we propose that intracellular molecule P62/A172 may play an
important part in the switch off/on signals necessary for bone resorbing cells to resorb bone. To this end, we will
study the molecular mechanism of P62 in action, and the interaction with its possible partners for the facilitation
of abnormal bone resorption. The clinical significance of this project is to: 1) enhance understanding of abnormal
bone resorption in Orthopaedic related diseases and conditions. 2) provide a strategy of drug development for the
treatment of these disease and conditions.

Research achievements (from final report):

The aim of this project is to study the role of p62 and p62 UBA mutants in osteocalstogenesis, pathological bone
destruction and signaling pathways related to Paget's disease of bone. Overproduction and activation of osteoclasts
underlines many lytic bone disorders such as osteoporosis, osteoarthritis and Paget's disease. Development of
strategies to control the formation or activities of osteoclasts has been a major focus of bone research. The
RANKL-induced NF-kB pathway is critical for osteoclastogenesis and osteoclastic bone resorption and, therefore
might represent a potential molecular target for the discovery of novel bone antiresorptive agents for the treatment
of lytic bone disorders. The proposed research addresses the fundamental role of the adapter molecule p62/A170
in RANKL-induced NF-kB activation and osteoclastogenesis. Unraveling the molecular and cellular mechanisms
by which p62 regulates osteoclast formation and activation will significantly contribute to the field of knowledge
and facilitate the development of novel and selective inhibitors for the treatment of lytic bone disorders.

Expected future outcomes:

The outcomes of the work proposed will help us to 1. Elucidate the role of adapter molecules p62/A170 in
RANKL-induced activation of NF-kB and osteoclastogenesis 2. Understand the role of PKC isoforms in RANKL-
induced activation of NF-kB and osteoclastogenesis, either via p62 dependent or independent pathway.

Name of contact:      Jiake Xu
Email of contact:     Jiake.xu@uwa.edu.au
                            NHMRC Research Achievements - SUMMARY

University of Wollongong

Grant ID:      354127                                             Start Year:       2005
CIA Name:      Prof Julie R Steele                                End Year:         2005
Main RFCD:     Medical Biotechnology                              Total funding:    $169,000.00
Admin Inst:    University of Wollongong                           Grant Type:       Development Grant


Title of research award: Reducing the burden of joint replacement: An innovative biofeedback device for post-
surgical rehabilitation

Lay Description (from application):

This project aims to develop a robust wearable device capable of providing immediate audible feedback with
respect to knee motion for enhanced post-knee replacement surgery rehabilitation, suitable for use by older people
both independently and supervised at home or in the clinic. As there is a current unmet need for such wearable
biofeedback devices, this project will lead to intellectual property generation, strengthened partnerships between
the involved parties and identification of an industry partner to commercialise the technology.

Research achievements (from final report):

This project aimed to improve the robustness of a wearable biofeedback joint sleeve for knee replacement
patients. The textile substrate had been identified previously. This textile substrate was initially coated with
polymers, metals and polymer-metal combinations to resolve the stability issues. Without extensive optimisation,
the metallated textiles were too conductive for the biofeedback device and polymer-coated textiles were
considered more appropriate. Therefore, we further optimised our conducting-polymer coating processes such that
the textile sensors were more stable within a variety of environmental conditions, including water, sweat and
humidity (30-80%). These processes were applied to a modified U-shaped sensor to enable robust attachment to
electronics and therefore a robust device. The sensors and electronics were then applied to the device and human
trials were conducted to assess the validity and reliability of the device when used in rehabilitation programs for
knee replacement patients. Seventeen subjects were assessed performing typical movements involved in
rehabilitation programs. Data from the biofeedback device were compared to data collected using an
optoelectronic motion analysis system. Human trial results revealed the joint sleeve was valid, in that the
programmed angle was equal (+ 10 degrees) to the angle at which the audible signal was emitted to the wearer,
and reliable, in that intraclass correlation coefficients calculated from the knee flexion angle at onset of the audible
signal ranged from R1 = 0.954 to 0.981. However, a disposable textile sensor is still required due to structural
creep changes within the textile itself leading to altered sensor performance with extended use (> 60 minutes) or
consistently large strains (> 50%). Therefore, the biofeedback joint sleeve was deemed appropriate for use in
rehabilitation programs for knee replacement patients.

Expected future outcomes:

The wearable biofeedback joint sleeve is being further developed for use in rehabilitation programs for knee
replacement patients. There is high end-user support for the device and, although interest has been received from
an international company who develop rehabilitaton devices, commercialisation of the device will be our focus for
the future.

Name of contact:       Professor Julie Steele
Email of contact:      julie_steele@uow.edu.au
                            NHMRC Research Achievements - SUMMARY
Victoria University

Grant ID:      181625                                            Start Year:      2002
CIA Name:      Prof Mark Hogarth                                 End Year:        2004
Main RFCD:     Humoral Immunology and Immunochemistry            Total funding:   $905,280.00
Admin Inst:    Victoria University                               Grant Type:      Standard Project Grant


Title of research award: Structure and function of receptors for IgG (FCgammaR)

Lay Description (from application):

This reasearch project is attempting to understand one of the most important mechanisms of resistance to
infectious disease and one of the most important mechanisms of induction of destructive inflammation in
autoimmune disease. These studies will define how blood proteins called antibodies, antibodies bind to the surface
of white blood cells via proteins called Fc receptors that activate these white blood cells. Under normal
circumstances this system provides resistance to infection but is involved in some of the most debilitating
diseases, including allergies, bleeding disorders called thrombocytopoenias, inflammation of blood vessels,
vasculitis, as well as aspects of rheumatoid arthritis. The successful conclusion of this project will result in
knowledge that will enable the development of more effective and highly specific therapeutic approaches to the
treatment of disease and a better understanding of the functioning of the immune system.

Research achievements (from final report):

The analysis of the interaction between antibodies and Fc receptors in this grant has led to the first understanding
of the precise mechanism that led to the activation of white blood cells by antibodies which are the primary
mechanims of resistance of infection and play a major role in destructive autoimmune diseases such as rheumatoid
arthritis. Specifically, we have: 1) identified unique organisational states in members of the Fc receptor family, 2)
solved the structures of allelic forms of FcgammaRIIa for the first time, 3) established crucial systems for
measuring receptor organisation, 4) defined functional important areas in the Fc receptor family, 5) shown that the
receptor organisation influenced antibody binding specificity.

Expected future outcomes:

This work will lead to the design of new anti-infllammatory protein and drugs that antagonise Fc receptor
function. In addition, understanding of Ig FcR interaction will lead to improved therapeutic antibodies for the
treatment of diseases such as cancer.

Name of contact:      Ms Susan Collins
Email of contact:     s.collins@ari.unimelb.edu.au
                            NHMRC Research Achievements - SUMMARY

Walter and Eliza Hall Institute

Grant ID:      171610                                            Start Year:       2001
CIA Name:      Dr Paul J Egan                                    End Year:         2004
Main RFCD:     Rheumatology and Arthritis                        Total funding:    $320,000.00
Admin Inst:    Walter and Eliza Hall Institute                   Grant Type:       Industry Fellowship


Title of research award: Development of cytokine signalling inhibitors for the treatment of rheumatoid arthritis.

Lay Description (from application):

No available Lay Description

Research achievements (from final report):

Suppressor of cytokine signalling (SOCS) proteins were evaluated as potential regulatory molecules that could
limit the extent and severity of rheumatoid arthritis. Mice lacking either SOCS-1 or SOCS-3 were found to
develop more severe arthritis in animal models, validating the strategy of over-expressing SOCS proteins within
arthritic joints as a potential therapeutic targets. Experiments designed to over-express SOCS proteins initially
used adenovirus vectors to deliver SOCS genes into the joint, although viral expression in the joint was not
sufficient to provide protection against arthritis. Alternative strategies to increase the expression of SOCS proteins
are currently being investigated. Blockade of the pro-inflammatory cytokine, GM-CSF, was also investigated as
an alternative strategy for the treatment chain of the human GM-CSF receptor and was found to block the activity
of GM-CSF in vivo. Clinical trials to test the safety and efficacy of this antibody are now under development.aof
rheumatoid arthritis. A fully human monoclonal antibody was developed against the

Expected future outcomes:

Inhibitors of the GM-CSF receptor will move forward into human clinical trials for the treatment of rheumatoid
arthritis. Systems designed to over-express SOCS proteins in synovial cells will be investigated to validate the use
of SOCS proteins as therapeutic agents for rheumatoid arthritis.

Name of contact:       Dr Paul Egan
Email of contact:      pegan@wehi.edu.au
                           NHMRC Research Achievements - SUMMARY

Grant ID:     305558                                           Start Year:      2004
CIA Name:     Prof Ian Wicks                                   End Year:        2005
Main RFCD:    Rheumatology and Arthritis                       Total funding:   $88,000.00
Admin Inst:   Walter and Eliza Hall Institute                  Grant Type:      Development Grant


Title of research award: DEVELOPMENT AND PRE-CLINICAL EVALUATION OF G-CSF INHIBITORS
FOR INFLAMMATORY JOINT DISEASE

Lay Description (from application):

G-CSF was originally identified as a cytokine regulating the production of neutrophils and haemopoietic stem
cells from the bone marrow and it is currently used clinically for these properties in bone marrow transplant
patients around the world. Anti-cytokine therapy with TNF blockade has recently been introduced for the
treatment of rheumatoid arthritis. However, not all patients respond to TNF inhibition. We have gathered
extensive data which shows that G-CSF also promotes inflammation in experimental models of inflammatory joint
disease. We propose to develop inhibitors of G-CSF as a novel form of anti-cytokine therapy for inflammatory
joint disorders, such as rheumatoid arthritis.

Research achievements (from final report):

This project was only part funded, but this was sufficient to generate, express and purify soluble versions of the
mouse and human G-CSF receptors as immunoglobulin fusion proteins. An assay for testing biological potency of
the inhibitors has been developed and the inhibitors were shown to successfully antagonise G-CSF effects. The
project provided the basis for optimisation of the inhibitors and a large scale production system.

Expected future outcomes:

The project has attracted keen biotechnology interest and led to a commercial collaboration to between Zenyth
Therapeutics, Murigen Therapeutrics and WEHI to fund development towards clincial trials.

Name of contact:      Ian Wicks
Email of contact:     wicks@wehi.edu.au
                           NHMRC Research Achievements - SUMMARY

Grant ID:      215408                                           Start Year:      2002
CIA Name:      Prof Ian Wicks                                   End Year:        2006
Main RFCD:     Rheumatology and Arthritis                       Total funding:   $250,000.00
Admin Inst:    Walter and Eliza Hall Institute                  Grant Type:      Practitioner Fellowship


Title of research award: Molecular mediators of murine inflammatory joint disease

Lay Description (from application):

No available Lay Description

Research achievements (from final report):

This practitioner fellowship allowed me to study the immunopathogenesis of inflammatory joint diseases and
identify new therapeutic targets for diseases such as rheumatoid arthritis. Two targets have been examined in
detail - G-CSF and GM-CSF. These molecules were discovered at WEHI and characterised as growth factors for
the blood cell system. My research shows these molecules also have important roles in inflammation. These
findings have led to collaborations with Australian biotechnology partners to develop and evaluate novel
antagonists of G- and GM-CSF for human cllinical trials. In parallel, I initiated and then collaborated with
colleagues on a clinical research program covering accelerated atherosclerosis in rheumatoid arthritis and joint
replacement surgery services for patients with arthritis. These initiatives led to new approaches to diagnosis and
prevention of atherosclerosis accompanying RA and a more rational prioritisation system for joint replacement
surgery.

Expected future outcomes:

New therapeutic agents for inflammatory diseases; diagnosing and preventing atherosclerosis in rheumatoid
arthritis; better management of joint replacement surgery services.

Name of contact:      Brad Allan
Email of contact:     allan@wehi.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      305523                                             Start Year:      2004
CIA Name:      Dr Paul J Egan                                     End Year:        2006
Main RFCD:     Rheumatology and Arthritis                         Total funding:   $438,375.00
Admin Inst:    Walter and Eliza Hall Institute                    Grant Type:      New Investigator


Title of research award: The role of SOCS-1 and SOCS-3 in regulating acute inflammatory arthritis

Lay Description (from application):

Rheumatoid arthritis (RA) is a chronic inflammatory disease which mainly targets joints. The disease causes
chronic joint pain, stiffness and loss of joint mobility, leading to increasing difficulty in carrying out day to day
activities. Treatment for RA has gradually improved, but remains inadequate for many patients. Although the
cause is unknown, progress has been made in understanding the molecular pathways which drive RA. The disease
is characterised by the production of high levels of inflammatory mediators called cytokines. This finding has led
to the development and introduction of specific cytokine inhibitors into clinical practice, although a significant
number of patients fail to respond to treatment. An alternative approach to develop new treatments for RA would
be to use the body's natural inhibitors to limit the actions of inflammatory cytokines. One such inhibitor is
Suppressor of Cytokine Signalling-1 (SOCS-1). Using animal models, we have shown that mice lacking SOCS-1
develop more severe arthritis and have identified the different cell types it acts on. Further studies are still needed
before SOCS-1 can be developed as a treatment for RA. We aim to identify the major cell type responsible for the
increased severity of disease seen when SOCS-1 is absent. This will allow for treatment to be targetted to the most
appropriate cells in the joint. We also aim to study the related molecule SOCS-3, to see whether it has similar
effects on inhibiting the severity of disease. These studies will provide more information on the activity of SOCS
proteins during inflammatory diseases in general and RA in particular and and may lead to new approaches for the
treatment of RA.

Research achievements (from final report):

Rheumatoid arthritis (RA) is caused by uncontrolled inflammation in the joints. Understanding the mechanisms by
which inflammation is controlled may lead to new therapies for the treatment of RA. The suppressor of cytokine
signalling (SOCS) proteins are a family of proteins that regulate the activity of cytokines, soluble proteins that can
drive inflammation. We have used genetically modified mice that lack genes for SOCS-1 and SOCS-3 to define
how SOCS proteins control inflammation in mouse models of RA. Following induction of inflammatory arthritis,
mice lacking SOCS-1 developed more severe joint inflammation than wild type mice due to an accumulation of
activated macrophages in the synovium. Mice lacking SOCS-3 in bone marrow-derived cells also developed more
severe arthritis, although the predominant inflammatory cell in these mice were neutrophils. This demonstrates
that both SOCS-1 and SOCS-3 are required to regulate the severity of inflammatory arthritis, although they
regulate the activity of different cell types. Mice lacking SOCS-3 only in T lymphocytes also developed more
severe inflammatory arthritis, although the severity was reduced compared to mice lacking SOCs-3 in all bone
marrow-derived cells. These results show that SOCS-1 and SOCS-3 are important in the regulation of
inflammatory arthritis and identify the key cell types in which these proteins act to control inflammation.

Expected future outcomes:

We have shown that SOCS-1 and SOCS-3 are important in regulating the severity of inflammatory arthritis and
the cell types in which SOCS proteins are most effective in controlling inflammation. Future outcomes would be
to identify ways of boosting the expression of SOCS proteins in these cell types and determining whether this
strategy could be used to develop new therapeutics.

Name of contact:       Dr Paul Egan
Email of contact:      pegan@wehi.edu.au
                             NHMRC Research Achievements - SUMMARY

Grant ID:      406645                                              Start Year:       2006
CIA Name:      Prof Ian Wicks                                      End Year:         2008
Main RFCD:     Orthopaedics                                        Total funding:    $331,000.00
Admin Inst:    Walter and Eliza Hall Institute                     Grant Type:       Standard Project Grant


Title of research award: The role of SOCS-3 in chondrocytes during development and disease

Lay Description (from application):

Cytokines are messenger proteins produced and secreted from one cell which then bind to specific receptors on
the surface of other cells. After binding, a series of intracellular events occurs, termed "signalling", that results in
the target cell changing its behaviour. Cytokine signalling, if allowed to proceed unchecked, can result in various
disease states. The suppressor of cytokine signalling (SOCS) proteins are key negative regulators of cytokine
signalling within the cell. They are induced by a wide range of stimuli, especially from a group called the "IL-6
family". We have preliminary data showing that cartilage cells (chondrocytes) normally produce a particular
SOCS protein, called SOCS-3. We have also shown that when SOCS-3 production is dysregulated, the
chondrocytes undergo excessive proliferation. Normal chondrocyte function is important during skeletal
development and diseases such as osteoarthritis are thought to result from abnormal chondrocyte behaviour. It is
likely that SOCS-3 has a key role in regulating chondrocyte function. The aim of this proposal is therefore to
examine the role of SOCS-3 in chondrocytes, during development and in disease. Much of our understanding of
the role of the SOCS proteins comes from the construction of mutant mice that lack a particular SOCS protein.
When mutant mice are made that lack SOCS-3 in the whole animal the mice die before birth and so virtually
nothing is known about the role of SOCS-3 in chondrocytes and the implications for cartilage in disease states,
such as arthritis. To answer this we will create mice that lack SOCS-3 specifically in their chondrocytes.
Evaluating the role of SOCS-3 in cartilage development and chondrocyte function during degenerative and
inflammatory disease states is potentially of major clinical importance in improving our understanding of arthritis
and of cartilage repair.

Research achievements (from final report):

We have developed a mouse that lacks a key regulatory protein, suppressor of cytokine signalling-3 (SOCS-3),
specifically in cartilage cells (chondrocytes) in order to understand its role in arthritis. SOCS-3 normally serves to
regulate the cellular response to inflammatory stimuli, such as cytokines We found that such mice were viable and
developed normally. However, when the mice were evaluated in experimental models of inflammatory arthritis
they developed markedly more severe disease than wild-type control mice. SOCS-3-deficient chondrocytes were
hyper-responsive to in vitro stimulation with the proinflammatory cytokine IL-1, showing enhanced nitric oxide
production. These findings suggest that SOCS-3 is critical in regulating the chondrocyte response to inflammatory
stimuli during arthritis. The data also show that chondrocytes themselves can significantly influence the
inflammatory response in the joint. These studies challenge the common perception that chondrocytes are targets
of, rather than contributors to, the inflammatory reponse in arthritis. Our studies also suggest that finding ways to
enhance SOCS-3 expression in chondrocytes could be therapeutically useful in the treatment of arthritis.

Expected future outcomes:

Our findings highlight the significant impact that cartilage cells can make to the disease response in arthritis. A
possible outcome is that it may be therapeutically beneficial to develop drugs that specifically control SOCS
proteins in chondrocytes.

Name of contact:       Michelle Trevorrow
Email of contact:      communityrelations@wehi.edu.au
                            NHMRC Research Achievements - SUMMARY

Grant ID:      356262                                           Start Year:      2005
CIA Name:      Dr Ben A Croker                                  End Year:        2009
Main RFCD:     Cellular Immunology                              Total funding:   $296,486.00
Admin Inst:    Walter and Eliza Hall Institute                  Grant Type:      CJ Martin Fellowship


Title of research award: Defining the components of Toll-like receptor signalling pathways using ENU
metagenesis.
Lay Description (from application):

No available Lay Description

Research achievements (from final report):

Mammals have evolved an array of mechanisms to sense microbes. These immune sentinels must distinguish self
from non-self to activate an immune response. The initiation, amplification and quenching of an immune response
is a carefully orchestrated process that eliminates invading pathogens while minimising collateral damage to host
tissues. This research focuses on proteins that restrict immune responses to prevent inflammatory diseases such as
sepsis, rheumatoid arthritis and psoriasis. This research has provided a unique insight into the innate immune
response in mammals. It demonstrates that despite a normal immune response to microbial infection, the host can
be profoundly susceptible to organ failure and death. Additional research will be required to identify human
populations at risk and also to identify similar genes that stabilise the host during infection.

Expected future outcomes:

The identification of an evolutionarily conserved protein required for the mammalian host to survive an immune
response points to the likelihood that other such proteins may exist. These proteins, as much as those that generate
the immune response itself, may determine the outcome of infection. Future research will seek to identify these
proteins and understand their role during infection.

Name of contact:      Michelle Trevorrow
Email of contact:     communityrelations@wehi.edu.au

				
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