Pathophysiology of Osteoarthritis PowerPoint Presentation

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Pathophysiology of Osteoarthritis Faith Dodd March 6, 2003

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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

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

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Factors responsible Ageing Genetics Hormones Mechanics

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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

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

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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

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Chondrocytes embedded in ECM, electron micrograph

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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

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

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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

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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

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Structure of Normal Cartilage

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Structure of Normal Cartilage

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Normal Cartilage, light micrograph

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Normal Cartilage

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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

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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

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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

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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

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Degenerative cartilage

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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

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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

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Synovial changes

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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

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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

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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

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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

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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

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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

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

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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

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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

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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

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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

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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

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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

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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

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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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