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