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Pathophysiology of Osteoarthritis
Faith DoddFaith DoddMarch 6, 2003March 6, 2003
Osteoarthritis
Osteoarthritis is an idiopathic diseaseOsteoarthritis is an idiopathic disease Characterized by degeneration of articular Characterized by degeneration of articular
cartilagecartilage Leads to fibrillation, fissures, gross Leads to fibrillation, fissures, gross
ulceration and finally disappearance of the ulceration and finally disappearance of the full thickness of articular cartilagefull thickness of articular cartilage
Osteoarthritis
Most common MSK disorder worldwideMost common MSK disorder worldwide Enormous social and economic Enormous social and economic
consequencesconsequences Multifactorial disorderMultifactorial disorder
Factors responsible
AgeingAgeing GeneticsGenetics HormonesHormones MechanicsMechanics
Pathologic lesions
Primary lesion appears to occur in cartilagePrimary lesion appears to occur in cartilage Leads to inflammation in synoviumLeads to inflammation in synovium Changes in subchondral bone, ligaments, Changes in subchondral bone, ligaments,
capsule, synovial membrane and capsule, synovial membrane and periarticular musclesperiarticular muscles
Normal Cartilage
Avascular, alymphatic and aneural tissueAvascular, alymphatic and aneural tissue Smooth and resilientSmooth and resilient Allows shearing and compressive forces to Allows shearing and compressive forces to
be dissipated uniformly across the jointbe dissipated uniformly across the joint
Structure of Normal Cartilage Chondrocytes are responsible for metabolism of Chondrocytes are responsible for metabolism of
ECMECM They are embedded in ECM and do not touch one They are embedded in ECM and do not touch one
another, unlike in other tissues in the bodyanother, unlike in other tissues in the body Chondrocytes depend on diffusion for nutrients and Chondrocytes depend on diffusion for nutrients and
therefore the thickness of cartilage is limitedtherefore the thickness of cartilage is limited Extracellular matrix is a highly hydrated Extracellular matrix is a highly hydrated
combination of proteoglycans and non-collagenous combination of proteoglycans and non-collagenous proteins immobilized within a type II collagen proteins immobilized within a type II collagen network that is anchored to bonenetwork that is anchored to bone
Chondrocytes embedded in ECM, electron micrograph
Structure of Normal Cartilage Divided into four morphologically distinct zones:Divided into four morphologically distinct zones: SuperficialSuperficial: flattened chondrocytes : flattened chondrocytes high collagen-to-proteoglycan ratio and high water high collagen-to-proteoglycan ratio and high water
content. content. Collagen fibrils form thin sheet parallel to Collagen fibrils form thin sheet parallel to
articular surface giving the superficial zone an articular surface giving the superficial zone an extremely high tensile stiffnessextremely high tensile stiffness
Restricts loss of interstitial fluid, encouraging Restricts loss of interstitial fluid, encouraging pressurization of fluidpressurization of fluid
Structure of Normal Cartilage
Transitional zone:Transitional zone: Small spherical chondrocytesSmall spherical chondrocytes Higher proteoglycan and lower water Higher proteoglycan and lower water
content than superficial zonecontent than superficial zone Collagen fibrils bend to form arcadesCollagen fibrils bend to form arcades
Structure of Normal Cartilage Radial Zone:Radial Zone: Occupies 90% of the column of articular cartilageOccupies 90% of the column of articular cartilage Proteoglycan content highest in upper radial zoneProteoglycan content highest in upper radial zone Collagen oriented perpendicular to subchondral Collagen oriented perpendicular to subchondral
bone providing anchorage to underlying calcified bone providing anchorage to underlying calcified matrixmatrix
Chondrocytes are largest and most synthetically Chondrocytes are largest and most synthetically active in this zoneactive in this zone
Structure of Normal Cartilage
Calcified zone:Calcified zone: Articular cartilage is attached to the Articular cartilage is attached to the
subchondral bone via a thin layer of subchondral bone via a thin layer of calcified cartilagecalcified cartilage
During injury and OA, the mineralization During injury and OA, the mineralization front advances causing cartilage to thinfront 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 Critically dependent on composition of
ECMECM Type II (IX&XI) provide 3D fibrous Type II (IX&XI) provide 3D fibrous
network which immobilizes PG and limits network which immobilizes PG and limits the extent of their hydrationthe extent of their hydration
When cartilage compresses H2O and When cartilage compresses H2O and solutes are expressed until repulsive forces solutes are expressed until repulsive forces from PGs balance load appliedfrom PGs balance load applied
Function of Normal Cartilage On removing load, PGs rehydrate restoring On removing load, PGs rehydrate restoring
shape of cartilageshape of cartilage Loading and unloading important for the Loading and unloading important for the
exchange of proteins in ECM and thus to exchange of proteins in ECM and thus to chondrocyteschondrocytes
Chondrocytes continually replace matrix Chondrocytes continually replace matrix macromolecules lost during normal macromolecules lost during normal turnoverturnover
Normal catabolism of cartilage Chondrocytes secrete degradative proteinases Chondrocytes secrete degradative proteinases
which are responsible for matrix turnoverwhich are responsible for matrix turnover These include: collagenases (MMP-1), gelatinases These include: collagenases (MMP-1), gelatinases
(MMP-2), stromolysin (MMP-3), aggrecanases(MMP-2), stromolysin (MMP-3), aggrecanases Normal cartilage metabolism is a highly Normal cartilage metabolism is a highly
regulated balance between synthesis and regulated balance between synthesis and degradation of the various matrix componentsdegradation of the various matrix components
OA cartilage
The equilibrium between anabolism and The equilibrium between anabolism and catabolism is weighted in favor of catabolism is weighted in favor of degradationdegradation
Disruption of the integrity of the collagen Disruption of the integrity of the collagen network as occurs early in OA allows network as occurs early in OA allows hyperhydration and reduces stiffness of hyperhydration and reduces stiffness of cartilagecartilage
Degenerative cartilage
Mechanisms responsible for degradation Catabolism of cartilage results in release of Catabolism of cartilage results in release of
breakdown products into synovial fluid breakdown products into synovial fluid which then initiates an inflammatory which then initiates an inflammatory response by synoviocytes response by synoviocytes
These antigenic breakdown products These antigenic breakdown products include: chondrointon sulfate, keratan include: chondrointon sulfate, keratan sulfate, PG fragments, type II collagen sulfate, PG fragments, type II collagen peptides and chondrocyte membranespeptides and chondrocyte membranes
Mechanisms responsible for degradation Activated synovial macrophages then recruit Activated synovial macrophages then recruit
PMNs establishing a synovitis PMNs establishing a synovitis They also release cytokines, proteinases and They also release cytokines, proteinases and
oxygen free radicals (superoxide and nitric oxide) oxygen free radicals (superoxide and nitric oxide) into adjacent and synovial fluidinto adjacent and synovial fluid
These mediators act on chondrocytes and These mediators act on chondrocytes and synoviocytes modifying synthesis of PGs, synoviocytes modifying synthesis of PGs, collagen, and hyaluronan as well as promoting collagen, and hyaluronan as well as promoting release of catabolic mediatorsrelease of catabolic mediators
Synovial changes
Cytokines in OA It is believed that cytokines and growth It is believed that cytokines and growth
factors play an important role in the factors play an important role in the pathophysiology of OApathophysiology of OA
ProinflammatoryProinflammatory cytokines are believed to cytokines are believed to play a pivotal role in the initiation and play a pivotal role in the initiation and development of the disease processdevelopment of the disease process
AntiinflammatoryAntiinflammatory cytokines are found in cytokines are found in increased levels in OA synovial fluidincreased levels in OA synovial fluid
Proinflammatory cytokines
TNF-TNF-α and IL-1 appear to be the major α and IL-1 appear to be the major cytokines involved in OA cytokines involved in OA
Other cytokines involved in OA are: IL-6, Other cytokines involved in OA are: IL-6, IL-8, leukemic inhibitory factor (LIF), IL-IL-8, leukemic inhibitory factor (LIF), IL-11, IL-1711, IL-17
TNF-α Formed as propeptide, converted to active form by Formed as propeptide, converted to active form by
TACE TACE Binds to TNF-Binds to TNF-α receptor (TNF-R) on cell α receptor (TNF-R) on cell
membranesmembranes TACE also cleaves receptor to form soluble TACE also cleaves receptor to form soluble
receptor (TNF-sR)receptor (TNF-sR) At low concentrations TNF-sR seems to stabilize At low concentrations TNF-sR seems to stabilize
TNF-TNF-α but at high concentrations it inhibits α but at high concentrations it inhibits activity by competitive bindingactivity by competitive binding
IL-1
Formed as inactive precursor, IL-1Formed as inactive precursor, IL-1β is β is active formactive form
Binds to IL-1 receptor (IL-1R), this receptor Binds to IL-1 receptor (IL-1R), this receptor is increased in OA chondrocytesis increased in OA chondrocytes
This receptor may be shed from membrane This receptor may be shed from membrane to form IL-1sR enabling it to compete with to form IL-1sR enabling it to compete with membrane associated receptorsmembrane associated receptors
TNF-α and IL-1 Induce joint articular cells to produce other Induce joint articular cells to produce other
cytokines such as IL-8, IL-6cytokines such as IL-8, IL-6 They stimulate proteasesThey stimulate proteases They stimulate PGE2 productionThey stimulate PGE2 production Blocking IL-1 production decreases IL-6 Blocking IL-1 production decreases IL-6
and IL-8 but not TNF-and IL-8 but not TNF-α α Blocking TNF-Blocking TNF-α using antibodies decreased α using antibodies decreased
production of IL-1, GM-CSF and IL-6production of IL-1, GM-CSF and IL-6
IL-6
Increases number of inflammatory cells in Increases number of inflammatory cells in synovial tissuesynovial tissue
Stimulates proliferation of chondrocytesStimulates proliferation of chondrocytes Induces amplification of IL-1 and thereby Induces amplification of IL-1 and thereby
increases MMP production and inhibits increases MMP production and inhibits proteoglycan productionproteoglycan production
IL-8
Chemotactic for PMNsChemotactic for PMNs Enhances release of TNF-Enhances release of TNF-α, IL-1 and IL-6 α, IL-1 and IL-6
Leukemic inhibitory factor (LIF) Enhances IL-1 And IL-8 expression in Enhances IL-1 And IL-8 expression in
chondrocytes and TNF-chondrocytes and TNF-α and IL-1 in α and IL-1 in synoviocytessynoviocytes
Regulates the metabolism of connective Regulates the metabolism of connective tissue, induces expression of collagenase tissue, induces expression of collagenase and stromolysinand stromolysin
Stimulates cartilage proteoglycan and NO Stimulates cartilage proteoglycan and NO productionproduction
Antiinflammatory cytokines
3 are spontaneously made in synovium and 3 are spontaneously made in synovium and cartilage and increased in OAcartilage and increased in OA
IL-4, IL-10, IL-13IL-4, IL-10, IL-13 Likely the body’s attempt to reduce the Likely the body’s attempt to reduce the
damage being produced by damage being produced by proinflammatory cytokines, these two proinflammatory cytokines, these two processes are not balanced in OAprocesses are not balanced in OA
IL-4 Decreases IL-1Decreases IL-1 Decreases TNF-Decreases TNF-α α Decreases MMPsDecreases MMPs Increases IL-Ra (competitive inhibitor of Increases IL-Ra (competitive inhibitor of
IL-1R)IL-1R) Increases TIMP (tissue inhibitor of Increases TIMP (tissue inhibitor of
metalloproteinases)metalloproteinases) Inhibits PGE2 releaseInhibits PGE2 release
IL-1Ra
Competitive inhibitor of IL-1R, not a Competitive inhibitor of IL-1R, not a binding protein of IL-1 and it does not binding protein of IL-1 and it does not stimulate target cellsstimulate target cells
Blocks PGE2 synthesisBlocks PGE2 synthesis Decreases collagenase productionDecreases collagenase production Decreases cartilage matrix productionDecreases cartilage matrix production
IL-10, IL-13
IL-10 decreases TNF-IL-10 decreases TNF-α by increasing α by increasing TNFsRTNFsR
IL-13 inhibits many cytokines, increases IL-13 inhibits many cytokines, increases production of IL-1Ra and blocks IL-1 production of IL-1Ra and blocks IL-1 productionproduction
Potential therapeutic applications
Neutralization of IL-1 and/or TNF-Neutralization of IL-1 and/or TNF-α α upregulation of MMP gene expressionupregulation of MMP gene expression
IL-1Ra suppressed MMP-3 transcription in IL-1Ra suppressed MMP-3 transcription in a rabbit modela rabbit model
Upregulation of antiinflammatory cytokinesUpregulation of antiinflammatory cytokines
Conclusions
Primary etiology of OA remains Primary etiology of OA remains undeterminedundetermined
Believed that cartilage integrity is Believed that cartilage integrity is maintained by a balance obtained from maintained by a balance obtained from cytokine driven-driven anabolic and cytokine driven-driven anabolic and catabolic processescatabolic processes
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