Pathophysiology of Osteoarthritis - PowerPoint - PowerPoint

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					Pathophysiology of Osteoarthritis




            Faith Dodd
           March 6, 2003
Osteoarthritis
 Osteoarthritis is an idiopathic disease
 Characterized by degeneration of articular
  cartilage
 Leads to fibrillation, fissures, gross
  ulceration and finally disappearance of the
  full thickness of articular cartilage
Osteoarthritis
 Most common MSK disorder worldwide
 Enormous social and economic
  consequences
 Multifactorial disorder
Factors responsible
 Ageing
 Genetics
 Hormones
 Mechanics
Pathologic lesions
 Primary lesion appears to occur in cartilage
 Leads to inflammation in synovium
 Changes in subchondral bone, ligaments,
  capsule, synovial membrane and
  periarticular muscles
Normal Cartilage
 Avascular, alymphatic and aneural tissue
 Smooth and resilient
 Allows shearing and compressive forces to
  be dissipated uniformly across the joint
Structure of Normal Cartilage
   Chondrocytes are responsible for metabolism of
    ECM
   They are embedded in ECM and do not touch one
    another, unlike in other tissues in the body
   Chondrocytes depend on diffusion for nutrients
    and therefore the thickness of cartilage is limited
   Extracellular matrix is a highly hydrated
    combination of proteoglycans and non-
    collagenous proteins immobilized within a type II
    collagen network that is anchored to bone
Chondrocytes embedded in ECM, electron
micrograph
Structure of Normal Cartilage
   Divided into four morphologically distinct zones:
   Superficial: flattened chondrocytes
   high collagen-to-proteoglycan ratio and high water
    content.
   Collagen fibrils form thin sheet parallel to
    articular surface giving the superficial zone an
    extremely high tensile stiffness
   Restricts loss of interstitial fluid, encouraging
    pressurization of fluid
Structure of Normal Cartilage
 Transitional zone:
 Small spherical chondrocytes
 Higher proteoglycan and lower water
  content than superficial zone
 Collagen fibrils bend to form arcades
Structure of Normal Cartilage
   Radial Zone:
   Occupies 90% of the column of articular cartilage
   Proteoglycan content highest in upper radial zone
   Collagen oriented perpendicular to subchondral
    bone providing anchorage to underlying calcified
    matrix
   Chondrocytes are largest and most synthetically
    active in this zone
Structure of Normal Cartilage
 Calcified zone:
 Articular cartilage is attached to the
  subchondral bone via a thin layer of
  calcified cartilage
 During injury and OA, the mineralization
  front advances causing cartilage to thin
Structure of Normal Cartilage
Structure of Normal Cartilage
Normal Cartilage, light micrograph
Normal Cartilage
Function of Normal Cartilage
 Critically dependent on composition of
  ECM
 Type II (IX&XI) provide 3D fibrous
  network which immobilizes PG and limits
  the extent of their hydration
 When cartilage compresses H2O and
  solutes are expressed until repulsive forces
  from PGs balance load applied
Function of Normal Cartilage
 On removing load, PGs rehydrate restoring
  shape of cartilage
 Loading and unloading important for the
  exchange of proteins in ECM and thus to
  chondrocytes
 Chondrocytes continually replace matrix
  macromolecules lost during normal
  turnover
Normal catabolism of cartilage
   Chondrocytes secrete degradative proteinases
    which are responsible for matrix turnover
   These include: collagenases (MMP-1), gelatinases
    (MMP-2), stromolysin (MMP-3), aggrecanases
   Normal cartilage metabolism is a highly
    regulated balance between synthesis and
    degradation of the various matrix components
OA cartilage
 The equilibrium between anabolism and
  catabolism is weighted in favor of
  degradation
 Disruption of the integrity of the collagen
  network as occurs early in OA allows
  hyperhydration and reduces stiffness of
  cartilage
Degenerative cartilage
Mechanisms responsible for
degradation
 Catabolism of cartilage results in release of
  breakdown products into synovial fluid
  which then initiates an inflammatory
  response by synoviocytes
 These antigenic breakdown products
  include: chondrointon sulfate, keratan
  sulfate, PG fragments, type II collagen
  peptides and chondrocyte membranes
Mechanisms responsible for
degradation
   Activated synovial macrophages then recruit
    PMNs establishing a synovitis
   They also release cytokines, proteinases and
    oxygen free radicals (superoxide and nitric oxide)
    into adjacent and synovial fluid
   These mediators act on chondrocytes and
    synoviocytes modifying synthesis of PGs,
    collagen, and hyaluronan as well as promoting
    release of catabolic mediators
Synovial changes
Cytokines in OA
 It is believed that cytokines and growth
  factors play an important role in the
  pathophysiology of OA
 Proinflammatory cytokines are believed to
  play a pivotal role in the initiation and
  development of the disease process
 Antiinflammatory cytokines are found in
  increased levels in OA synovial fluid
Proinflammatory cytokines
 TNF-α and IL-1 appear to be the major
  cytokines involved in OA
 Other cytokines involved in OA are: IL-6,
  IL-8, leukemic inhibitory factor (LIF), IL-
  11, IL-17
TNF-α
   Formed as propeptide, converted to active form by
    TACE
   Binds to TNF-α receptor (TNF-R) on cell
    membranes
   TACE also cleaves receptor to form soluble
    receptor (TNF-sR)
   At low concentrations TNF-sR seems to stabilize
    TNF-α but at high concentrations it inhibits
    activity by competitive binding
IL-1
 Formed as inactive precursor, IL-1β is
  active form
 Binds to IL-1 receptor (IL-1R), this receptor
  is increased in OA chondrocytes
 This receptor may be shed from membrane
  to form IL-1sR enabling it to compete with
  membrane associated receptors
TNF-α and IL-1
 Induce joint articular cells to produce other
  cytokines such as IL-8, IL-6
 They stimulate proteases
 They stimulate PGE2 production
 Blocking IL-1 production decreases IL-6
  and IL-8 but not TNF-α
 Blocking TNF-α using antibodies decreased
  production of IL-1, GM-CSF and IL-6
IL-6
 Increases number of inflammatory cells in
  synovial tissue
 Stimulates proliferation of chondrocytes
 Induces amplification of IL-1 and thereby
  increases MMP production and inhibits
  proteoglycan production
IL-8
 Chemotactic for PMNs
 Enhances release of TNF-α, IL-1 and IL-6
Leukemic inhibitory factor (LIF)
 Enhances IL-1 And IL-8 expression in
  chondrocytes and TNF-α and IL-1 in
  synoviocytes
 Regulates the metabolism of connective
  tissue, induces expression of collagenase
  and stromolysin
 Stimulates cartilage proteoglycan and NO
  production
Antiinflammatory cytokines
 3 are spontaneously made in synovium and
  cartilage and increased in OA
 IL-4, IL-10, IL-13
 Likely the body’s attempt to reduce the
  damage being produced by
  proinflammatory cytokines, these two
  processes are not balanced in OA
IL-4
 Decreases IL-1
 Decreases TNF-α
 Decreases MMPs
 Increases IL-Ra (competitive inhibitor of
  IL-1R)
 Increases TIMP (tissue inhibitor of
  metalloproteinases)
 Inhibits PGE2 release
IL-1Ra
 Competitive inhibitor of IL-1R, not a
  binding protein of IL-1 and it does not
  stimulate target cells
 Blocks PGE2 synthesis
 Decreases collagenase production
 Decreases cartilage matrix production
IL-10, IL-13
 IL-10 decreases TNF-α by increasing
  TNFsR
 IL-13 inhibits many cytokines, increases
  production of IL-1Ra and blocks IL-1
  production
Potential therapeutic applications
 Neutralization of IL-1 and/or TNF-α
  upregulation of MMP gene expression
 IL-1Ra suppressed MMP-3 transcription in
  a rabbit model
 Upregulation of antiinflammatory cytokines
Conclusions
 Primary etiology of OA remains
  undetermined
 Believed that cartilage integrity is
  maintained by a balance obtained from
  cytokine driven-driven anabolic and
  catabolic processes
References
   Aigner T, Kim H. Apoptosis and Cellular Vitality, Issues in
    Osteoarthritic Cartilage degeneration. Arthritis Rheum 2002;46:1986-
    1996.
   Aigner T, McKenna L. Molecular pathology and pathobiology of
    osteoarthritic cartilage. Cell Mol Life Sci 2002;59:5-18.
   Fernandes J, Martel-Pelletier J, Pelletier JP. The role of cytokines in
    osteoarthritis pathophysiology. Biorheology 2002; 39:237-246.
   Ghosh P, Smith M. Osteoarthritis, genetic and molecular mechanisms.
    Biogerontology 2002;3:85-88.
   Insall S, Scott W. Surgery of the Knee 3rd Ed. New York: Churchill
    Livingstone 2001;13-38, 317-325.
   Martel-Pelletier J. Pathophysiology of osteoarthritis. Osteoarthritis
    Cart 1999;7:371-373.
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