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    Pathophysiology of Osteoarthritis

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    Dhika Ardiansyah
    Osteoarthritis is characterized by the degeneration of articular cartilage leading to its eventual disappearance. It is a multifactorial disorder influenced by age, genetics, hormones, and mechanics. While the primary lesion occurs in cartilage, it leads to inflammation in surrounding tissues like the synovium and changes in subchondral bone. Normal cartilage consists of chondrocytes embedded in an extracellular matrix of proteoglycans and collagen that allows it to dissipate forces across joints. In osteoarthritis, there is an imbalance between the anabolic and catabolic processes in cartilage that favors degradation over synthesis of new matrix. Proinflammatory cytokines like TNF-α and IL-1 are thought to play a key role by stimulating cartilage

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    Pathophysiology of Osteoarthritis

    Uploaded by

    Dhika Ardiansyah
    214 views42 pages
    Osteoarthritis is characterized by the degeneration of articular cartilage leading to its eventual disappearance. It is a multifactorial disorder influenced by age, genetics, hormones, and mechanics. While the primary lesion occurs in cartilage, it leads to inflammation in surrounding tissues like the synovium and changes in subchondral bone. Normal cartilage consists of chondrocytes embedded in an extracellular matrix of proteoglycans and collagen that allows it to dissipate forces across joints. In osteoarthritis, there is an imbalance between the anabolic and catabolic processes in cartilage that favors degradation over synthesis of new matrix. Proinflammatory cytokines like TNF-α and IL-1 are thought to play a key role by stimulating cartilage

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    Osteoarthritis is characterized by the degeneration of articular cartilage leading to its eventual disappearance. It is a multifactorial disorder influenced by age, genetics, hormones, and mechanics. While the primary lesion occurs in cartilage, it leads to inflammation in surrounding tissues like the synovium and changes in subchondral bone. Normal cartilage consists of chondrocytes embedded in an extracellular matrix of proteoglycans and collagen that allows it to dissipate forces across joints. In osteoarthritis, there is an imbalance between the anabolic and catabolic processes in cartilage that favors degradation over synthesis of new matrix. Proinflammatory cytokines like TNF-α and IL-1 are thought to play a key role by stimulating cartilage

    Copyright:

    © All Rights Reserved
    Download as PPT, PDF, TXT or read online from Scribd
    Download as ppt, pdf, or txt
    214 views42 pages

    Pathophysiology of Osteoarthritis

    Uploaded by

    Dhika Ardiansyah
    Osteoarthritis is characterized by the degeneration of articular cartilage leading to its eventual disappearance. It is a multifactorial disorder influenced by age, genetics, hormones, and mechanics. While the primary lesion occurs in cartilage, it leads to inflammation in surrounding tissues like the synovium and changes in subchondral bone. Normal cartilage consists of chondrocytes embedded in an extracellular matrix of proteoglycans and collagen that allows it to dissipate forces across joints. In osteoarthritis, there is an imbalance between the anabolic and catabolic processes in cartilage that favors degradation over synthesis of new matrix. Proinflammatory cytokines like TNF-α and IL-1 are thought to play a key role by stimulating cartilage

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    © All Rights Reserved
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    Download as ppt, pdf, or txt
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    Osteoarthritis is characterized by the degeneration of articular cartilage and leads to fibrillation, fissures, and thinning of cartilage. It is a multifactorial disease influenced by age, genetics, hormones, and mechanics.

    Osteoarthritis is characterized by degeneration of articular cartilage. It is an idiopathic disease that leads to fibrillation, fissures, gross ulceration and finally disappearance of the full thickness of articular cartilage.

    The four zones of normal cartilage are: superficial, transitional, radial, and calcified. Each zone has distinct characteristics in terms of chondrocyte shape and distribution as well as collagen and proteoglycan content.

    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 noncollagenous 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- 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), IL11, IL-17

    TNF-

    Formed as propeptide, converted to active form by TACE Binds to TNF- 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- but at high concentrations it inhibits activity by competitive binding

    IL-1
    Formed as inactive precursor, IL-1 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- 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- Blocking TNF- 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-, IL-1 and IL-6

    Leukemic inhibitory factor (LIF)


    Enhances IL-1 And IL-8 expression in chondrocytes and TNF- 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 bodys 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- 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- 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- 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;46:19861996. 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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