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					  Spring 2010
                                                               Musculoskeletal
                                                                Messenger
Inside this issue:                      University of Pennsylvania Penn Center for Musculoskeletal Disorders

PCMD Annual Scientific Sympo- 2
sium, P30 Renewal grant, Spot-
light on PCMD Member research                  Institute on Aging Annual Retreat –April 28, 2010
Spotlight on PCMD Member          3
research                                The Penn Center for Muscu-         Director of the Maine Center for      Function and Vitamin D in
                                        loskeletal Disorders will co-      Osteoporosis Research and             Adults with Chronic Kidney Dis-
Upcoming Events                   4
                                                                           Education. Dr. Rosen will pre-
                                        sponsor the Institute on Aging                                           ease."
                                        (IOA) 2010 Sylvan M. Cohen         sent "Who is Keeping Time? The        The annual Poster Session on
                                        Annual Retreat with Poster Ses-    Role of Clock Genes in Regulat-       Aging will follow the lectures
  Penn Center for Musculoskeletal                                          ing Body Composition."
                                        sion on Aging which will take                                            and is open to all who wish to
               Disorders
 University of Pennsylvania School of
                                        place April 28, 2010, in Hous-     Featured PENN presenters are          participate. Prizes will be
               Medicine                 ton Hall here on Penn's cam-       Robert J. Pignolo, MD, PhD,           awarded to the top posters in
 424 Stemmler Hall, 3450 Hamilton       pus.                               Assistant Professor of Medicine,      each category.
                 Walk                   The title of the retreat will be   and Director, Ralston-Penn            Registration is required to at-
    Philadelphia, PA 19104-6081         "Structurally Sound: Bone          Clinic for Osteoporosis & Re-         tend and/or present a poster.
                                        Health and Aging" and there will   lated Bone Disorders, and Mary        Lunch will be provided to those
       Phone: 215-898-8653
                                        be a poster session. The retreat   Leonard, MD, MSCE, Professor          who register.
        Fax: 215-573-2133
                                        will take place from 11:30 am—     of Pediatrics and Epidemiology.       There is no charge to attend
     www.med.upenn,edu/pcmd
                                        5:30 pm.                           Dr. Pignolo's presentation will       and the public is welcome. For
If you have any news or information     Serving as the Sylvan M. Cohen     discuss "The Biological Basis for     more information about this
that you would like included in the     Visiting Scholar is Clifford J.    Alternative Approaches to Os-         event, please visit:
                                        Rosen, MD, Senior Scientist at     teoporosis Treatment" while Dr.       http://www.med.upenn.edu/
next issue of this newsletter, please
                                        the Maine Medical Center Re-       Leonard will speak about her
email us at:
                                                                                                                 aging
                                        search Institute and Former        work in "Bone Structure, Muscle
centermd@mail.med.upenn.edu


                                        Institute on Aging/PCMD Co-Sponsored Pilot Grant Recipients
                                   The University of Pennsylvania          Kurt D. Hankenson, D.V.M., M.S.,      with aging. By extension, he also
                                   Institute on Aging (IOA) has            Ph.D., will receive funding for his   hypothesizes that activating
                                   awarded ten investigators with          pilot grant titled “Notch Signaling   Notch signaling will promote bone
                                   one year of funding each for their      in Bone Regeneration.”                regeneration.
Did you know that funds are avail- pilot grant projects with a start
able to support projects within                                            Hankenson’s grant focuses on          The third recipient is Eileen
                                   date of July 1, 2010. Our PCMD          Notch signaling, one possible
each Research Core (in addition to has co-sponsored this competi-                                                Shore, Ph.D., whose pilot grant is
                                                                           explanation for the healing deficit   titled “Modulation of Progenitor
the Pilot Grant Program)? For      tion along with The Bingham Trust       that is observed in muscle, with      Cell Differentiation through BMP
more information, please contact and 3 musculoskeletal grants              age. Notch signaling is also active   Signaling.” Dr. Shore’s pilot grant
the Core Directors-                were awarded.                           during bone regeneration; how-        focuses on understanding key
Donald Baldwin, Ph.D.-             Olena Jacenko, Ph.D., will receive      ever, there has not been a report     molecular factors that control
dbaldwin@mail.med,upenn.edu        funding to support her project          of decreased Notch signaling in       differentiation of stem cells and
(microarray)                       titled “Aging of the Hematopoietic      bone associated with age nor          the cellular mechanisms that
                                   Niche.” Dr. Jacenko will seek to        associating defects in healing        regulate specific cell fate deci-
Dawn Elliott, Ph.D.-               understand the cause of underly-        with alterations in Notch. Hanken-    sions and narrow the gap in our
delliott@mail.med.upenn.edu        ing age-related changes including       son hypothesizes that Notch sig-      knowledge of these processes
(structure-function biomechanics) reduced bone mass, diminished            naling is reduced in aged mesen-      that are relevant to aging-related
                                   blood formation, and deficient          chymal stem cells (MSC). This         bone loss.
Felix Wehrli, Ph.D.-
                                   immune function leading to bone         contributes to a decrease in MSC
wehrli@mail.med.upenn.edu                                                  number and function and defec-
                                   cancer.
(imaging).                                                                 tive bone regeneration observed
Page 2                                                                                                             The Musculoskeletal Messenger



   PCMD Annual Scientific Symposium Scheduled for Nov. 17, 2010
   The PCMD is looking forward to        speak on Musculoskeletal Re-         Last year’s event featured 47
   the 7th Annual Scientific Sym-        generative Medicine.                 posters and boasted over 180
   posium which will take place on       The symposium will include a         registrants. We are expecting
   November 17, 2010. The key-           continental breakfast, moder-        another successful event this
   note speaker will be Michael J.       ated scientific sessions, lunch      coming November. Please mark
   Yaszemski, M.D., Ph.D., Profes-       and poster sessions.                 your calendar and be sure to
   sor of Orthopaedics and Bioen-                                             check the PCMD website in the
                                         The day will conclude with Dr.
   gineering at the Mayo Clinic,                                              coming months for updated
                                         Yaszemski’s lecture and the
   and the Director of the Tissue                                             information about the sympo-
                                         presentation of poster awards.
   Engineering and Biomaterials                                               sium.
   Laboratory. Dr. Yaszemski will



   PCMD Center Grant Up for Renewal by NIH
   The NIH P30 Grant which funds         facing with other P30 centers        membership category might in-        We always welcome your sugges-
   our PCMD center is up for re-         locally and nationally, improving    clude grant writing assistance       tions and comments for ways to
   newal this summer. Our center is      the PCMD website to include          and travel grants so that the As-    improve the Center so that it may
   among the country’s five P30          more information about research      sociate Members would be aided       better serve you, the muscu-
   centers, three of which will be       core opportunities and pricing for   in attending musculoskeletal         loskeletal community here at
   competing for renewal this round.     members, and questions related       research conferences where re-       Penn. Therefore, if there are
   Recently, PCMD Director Lou           to foci for future research.         search was being presented.          other ideas or initiatives that you
   Soslowsky met with Center core        Another exciting idea that the       Thanks to all PCMD members           would like the PCMD to under-
   directors and associate directors     PCMD leadership is considering       who responded to our email re-       take, please e-mail us at:
   to discuss what goals and objec-      is the creation of a PCMD Associ-    quests for paper and grant cita-     centermd@mail.med.upenn.edu.
   tives they would like to accom-       ate Membership category which        tions—these will be incorporated
   plish within the next few years.      would be open to Penn grad stu-      in our progress report to the NIH
   These goals include: partnering       dents, post-docs and research        and serve as important metrics of
   with other centers and institutes     staff. The benefits of this new      our activities and successes.
   within the Penn community, inter-


   Research Updates from PCMD Members

   T1r MRI Studies on Articular Cartilage of Human Knee—Ravinder Reddy, Ph.D.
   Osteoarthritis (OA) affects more      pain. Because of the long natural    MRI, a novel imaging method that     Initial data shows a significant
   than half of the population above     history of OA (10-20 years), vali-   has the ability to generate en-      (p<0.001) mean T1ρ value in-
   the age of 65 and the economic        dating the efficacy of potential     dogenous contrast that is sensi-     crease between the 3 and 9-
   costs in the US from OA have          disease modifying drugs in hu-       tive to in vivo proteoglycan con-    month time points for all individu-
   been estimated to be more than        mans will require a technique        tent. To determine the efficacy of   als recruited. These preliminary
   1% of the gross domestic product.     that can directly assess their       this method in tracking molecular    results show the potential of T1r
   A feature of idiopathic OA is the     effect on the macromolecular         changes in early OA, we are study-   MRI in tracking the disease pro-
   degradation of proteoglycan mac-      matrix.                              ing correlation between arthro-      gression in morphologically intact
   romolecules within hyaline articu-    Arthroscopy, an invasive proce-      scopically confirmed chondro-        human cartilage in vivo.
   lar cartilage. There is no cure for   dure, is currently the gold stan-    malacia and proteoglycan-
   the disease and treatments pri-       dard to diagnose this pathology.     induced changes in T1rMRI.
   marily focused on alleviating the     Our group has developed, T1ρ


                                                                                                                          Figure 1: Representative
                                                                                                                          axial patella view of T1r map
                                                                                                                          overlay. A - Age Matched
                                                                                                                          control,B - 3 months post
                                                                                                                          arthroscopy, C- 9 months
                                                                                                                          post arthroscopy. Color bar
                                                                                                                          of T1r values in millisec-
                                                                                                                          onds.
                    A                                     B                                   C
Spring 2010                                                                                                                                                      Page 3


Research Updates from PCMD Members
Identifying mechanical signals for muscle growth-Elisabeth R. Barton, Ph.D.
Hard and soft tissues share important physio-            conversion of muscle stretch to an appro-
logical properties. For example, the ability to          priate signal for maintaining muscle integ-
convert mechanical load to signals for tissue            rity. We utilize both isolated murine skeletal
growth not only makes bones stronger, but                muscle and cell culture systems to probe
also helps to maintain skeletal muscle mass.             into how the sarcoglycans fit into the load-
For the last few years, my lab has been exam-            sensor picture (See figure right). These
ining the membrane complexes that sense                  studies contribute to understanding the
muscle load. Like most other cell types, the             pathogenesis of the muscular dystrophies,
integrin complex, which spans the muscle                 where mutations in the DGC cause muscle
plasma membrane, senses mechanical                       fragility and degeneration, and also to find-
forces, and through its links to signal trans-           ing ways to maintain muscle mass when
duction cascades, drives muscle growth. How-             the tissue lacks load signals, as in bed rest
ever, an additional membrane complex, the                or space travel. Support for this research
dystrophin glycoprotein complex (DGC), has               includes grants from NIH, NASA, and the
emerged as a complementary mechanical                    American Heart Association.
signal transduction system for skeletal mus-
cle. The sarcoglycans, which are part of the
DGC appear to be important for regulating the


                                                                                             Above: Model for mechanical sensors in skeletal muscle. The dystrophin
                                                                                             glycoprotein complex is poised to detect mechanical changes. Mechanical
                                                                                             perturbation, induced by stretch or contraction or both (shown in large red
                                                                                             arrows), can cause membrane distortions that are sensed by proteins span-
                                                                                             ning the sarcolemma, including the integrins and sarcoglycans (SG). This
                                                                                             leads to activation of the MAPK pathways (represented by ERK) and also
                                                                                             phosphorylation of SG complex members. FAK is kinase which is likely to
                                                                                             mediate these changes.




Quantification of Age Dependent Molecular Changes in Guinea Pig OA Model using T1ρ MRI-Ravinder Reddy, Ph.D.
Osteoarthritis (OA) is a degenerative      and genetic factors. T1ρ MRI is a         month old cohort and 5, 7, and 9
joint disease, which causes severe         novel imaging method that has the         month old cohorts. A non-significant
pain and is associated with compro-        ability to generate endogenous con-       increase of mean T1ρ (mean p<0.11)
mised quality of life and imparts heavy    trast that is sensitive to in vivo pro-   was found between the three older
toll on the health care system. Knee       teoglycan content which is a key factor   cohorts. Analysis of the skewness of
and hip OA cases are primarily contrib-    in early stage OA development.            the data shows significant differences
uting to chronic disability amongst the                                              (p<0.001) between the 3 month old
elderly population. Currently there is     The purpose of this study was to dem-     cohort and the three older cohorts.
no cure for the disease and therapeu-      onstrate the efficacy of T1ρ MRI in       Data demonstrates that proteoglycan
tic interventions are primarily targeted   quantifying age-dependent, spontane-      loss has already occurred by 5 months
to symptomatic relief. Various animal      ous osteoarthritic changes in the         of age with late stage morphological
models have been developed to study        Dunkin-Hartley guinea pig model over      changes (cartilage thinning and loss)
the progression of OA. Guinea pigs are     a period of 10 months. Four age           occurring by 9 months.
unique in that OA progression occurs       cohorts (3, 5, 7, and 9 month old)
spontaneously and develops much            were scanned with the T1ρ MRI proto-      These studies demonstrate the poten-
quicker than in other models. Age          col. Immediately following imaging,       tial of T1ρ mapping in quantifying
dependent biochemical analysis of the      animals were sacrificed and tissue        early molecular changes associated
Dunkin-Hartley guinea pig stifle has       was harvested for histological analysis   with spontaneous cartilage degenera-
been studied extensively demonstrat-       for confirmation of OA. For age-          tion by 5 months of age.
ing spontaneous OA progression.            dependent T1ρ analysis, a one-tailed
Evidence suggests a multi-factorial        unpaired t-test with unequal variance     T1ρ MRI coupled with the spontane-
etiology of OA by combinations of          was performed to determine signifi-       ous OA model potentially enable test-
biomechanical (non-optimal loading         cant changes between cohorts. There       ing of disease modifying osteoarthritis   Please turn to page 4 for image
stresses/trauma), biochemical              was a significant (p<0.001) increase      drugs in vivo in a time efficient and     corresponding to this research
(breakdown of proteoglycan matrix),        of mean T1ρ value between the 3           cost effective manner.
Below-Image from Dr. Reddy’s research (story, page 3)

          3 month                        5 month                        7 month                         9 month




0 40           140              0   40         140            0   40         120              0 40           180

Figure 1 - Representative T1ρ map overlays of four age cohorts with T1ρ histogram distributions. Color-bar values are in
milliseconds.




   Upcoming Events
   PCMD Visiting Professorship                    Sylvan M. Cohen Annual Retreat with              Center for Bone Health
                                                  Poster Session on Aging 2010
   Series                                                                                          Conference
                                                  Structurally Sound: Bone Health and Aging
   Tuesday, May 18, 2010, 1:00-                                                                    Friday, May 14, 2010, 12:00-1:00
   2:00pm/BRB 251                                 The 2010 Sylvan M. Cohen Annual Retreat with     pm/Room TBA
   Scott A. Rodeo, MD                             Poster Session on Aging will take place April
                                                                                                   Optimizing Bone Health in Children
                                                  28, 2010, in Houston Hall here on Penn's cam-
   “The Role of Mechanical Loading in                                                              and Adolescents
                                                  pus.
   Tendon-to-Bone Healing: Our Experi-                                                             Catherine Gordon, M.D., MSc, Direc-
                                                  The Institute on Aging will be partnering with
   ence with Small Animal Models”                                                                  tor Bone Health Program, Children’s
                                                  the Penn Center for Musculoskeletal Disorders
                                                  to present the 2010 retreat, with its focus on   Hospital Boston
   Professor of Orthopaedic Surgery,
   Weill Cornell Medical College, New             "Structurally Sound: Bone Health and Aging"
   York, NY                                       and annual poster session.                       For more information, contact:
                                                  There is no charge to attend and the public is   Michael A. Levine, M.D., FAAP, FACP
   Attending Orthopaedic Surgeon, New             welcome. For more information about this         Chief, Division of Endocrinology and
   York-Presbyterian Hospital                     event, please visit:                             Diabetes
   Attending Orthopaedic Surgeon, Hospi-          http://www.med.upenn.edu/aging/index.shtml       The Children's Hospital of Philadel-
   tal for Special Surgery, New York, NY                                                           phia
                                                                                                   215-590-3618 - phone
                                                                                                   215-590-3053 - fax
                                                                                                   levinem@chop.edu