Pathophysiology of Osteoarthritis

Faith DoddFaith Dodd

March 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 Chondrocytes depend on diffusion for nutrients and therefore the thickness of cartilage is limitedand therefore the thickness of cartilage is limited

Extracellular matrix is a highly hydrated Extracellular matrix is a highly hydrated combination of proteoglycans and non-combination of proteoglycans and non-collagenous proteins immobilized within a type II collagenous proteins immobilized within a type II collagen network that is anchored to bonecollagen network 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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