Pathophysiology of Osteoarthritis

Pathophysiology of Osteoarthritis - Pathophysiology of...

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