1. Pathophysiology of Osteoarthritis
Faith Dodd
March 6, 2003

2. 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

4. Osteoarthritis Most common MSK disorder worldwide
Enormous social and economic consequences
Multifactorial disorder

5. Factors responsible
Ageing
Genetics
Hormones
Mechanics

6. 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

7. Normal Cartilage Avascular, alymphatic and aneural tissue
Smooth and resilient
Allows shearing and compressive forces to be dissipated uniformly across the joint

8. 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

9. Chondrocytes embedded in ECM, electron micrograph

10. 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

11. Structure of Normal Cartilage
Transitional zone:
Small spherical chondrocytes
Higher proteoglycan and lower water content than superficial zone
Collagen fibrils bend to form arcades

12. 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

13. 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

14. Structure of Normal Cartilage

15. Structure of Normal Cartilage

16. Normal Cartilage, light micrograph

17. Normal Cartilage

18. 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

19. 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

20. 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

21. 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

22. Degenerative cartilage

23. 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

24. 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

25. Synovial changes

26. 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

27. 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

28. 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

29. 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

30. 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

31. 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

32. IL-8
Chemotactic for PMNs
Enhances release of TNF-α, IL-1 and IL-6

33. 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

35. 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

36. 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

37. 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

38. 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

39. 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

40. 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

41. References
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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:
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,
Martel-Pelletier J. Pathophysiology of osteoarthritis. Osteoarthritis Cart 1999;7:

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