Download - Pathophysiology+of+Osteoarthritis
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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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Most common MSK disorder worldwide Enormous social and economic
consequences Multifactorial disorder
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Ageing Genetics Hormones Mechanics
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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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Avascular, alymphatic and aneural tissue
Smooth and resilient Allows shearing and compressive forces
to be dissipated uniformly across the joint
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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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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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Transitional zone: Small spherical chondrocytes Higher proteoglycan and lower water
content than superficial zone Collagen fibrils bend to form arcades
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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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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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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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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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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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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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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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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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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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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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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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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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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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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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Chemotactic for PMNs Enhances release of TNF-α, IL-1 and IL-
6
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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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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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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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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 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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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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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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