pa tho physiology of osteoarthritis

8/7/2019 Pa Tho Physiology of Osteoarthritis

1/40

Pathophysiology of Osteoarthritis


2/40

Osteoarthritis Osteoarthritis is an idiopathic diseaseOsteoarthritis is an idiopathic disease

Characterized by degeneration of articularCharacterized by degeneration of articular

cartilagecartilage

Leads to fibrillation, fissures, grossLeads to fibrillation, fissures, gross

ulceration and finally disappearance of theulceration and finally disappearance of the

full thickness of articular cartilagefull thickness of articular cartilage


3/40


4/40

Osteoarthritis Most common MSK disorder worldwideMost common MSK disorder worldwide

Enormous social and economicEnormous social and economic

consequencesconsequences

Multifactorial disorderMultifactorial disorder


5/40

Factors responsible

AgeingAgeing

GeneticsGenetics

HormonesHormones

MechanicsMechanics


6/40

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 andcapsule, synovial membrane and

periarticular musclesperiarticular muscles


7/40

Normal Cartilage

Avascular, alymphatic and aneural tissueAvascular, alymphatic and aneural tissue

Smooth and resilientSmooth and resilient

Allows shearing and compressive forces toAllows shearing and compressive forces to

be dissipated uniformly across the jointbe dissipated uniformly across the joint


8/40

Structure ofN

ormal Cartilage Chondrocytes are responsible for metabolism ofChondrocytes are responsible for metabolism of

ECMECM

They are embedded in ECM and do not touch oneThey are embedded in ECM and do not touch oneanother, unlike in other tissues in the bodyanother, unlike in other tissues in the body

Chondrocytes depend on diffusion for nutrientsChondrocytes depend on diffusion for nutrientsand therefore the thickness of cartilage is limitedand therefore the thickness of cartilage is limited

Extracellular matrix is a highly hydratedExtracellular matrix is a highly hydratedcombination of proteoglycans and noncombination of proteoglycans and non--collagenous proteins immobilized within a type IIcollagenous proteins immobilized within a type IIcollagen network that is anchored to bonecollagen network that is anchored to bone


9/40

Chondrocytes embedded in ECM, electronmicrograph


10/40

Structure ofN

ormal Cartilage Divided into four morphologically distinct zones:Divided into four morphologically distinct zones:

SuperficialSuperficial: flattened chondrocytes: flattened chondrocytes

high collagenhigh collagen--toto--proteoglycan ratio and high waterproteoglycan ratio and high watercontent.content.

Collagen fibrils form thin sheet parallel toCollagen fibrils form thin sheet parallel toarticular surface giving the superficial zone anarticular surface giving the superficial zone an

extremely high tensile stiffnessextremely high tensile stiffness Restricts loss of interstitial fluid, encouragingRestricts loss of interstitial fluid, encouraging

pressurization of fluidpressurization of fluid


11/40

Structure ofN

ormal Cartilage Transitional zone:Transitional zone:

Small spherical chondrocytesSmall spherical chondrocytes

Higher proteoglycan and lower waterHigher proteoglycan and lower water

content than superficial zonecontent than superficial zone

Collagen fibrils bend to form arcadesCollagen fibrils bend to form arcades


12/40

Structure ofN

ormal 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 subchondralCollagen oriented perpendicular to subchondral

bone providing anchorage to underlying calcifiedbone providing anchorage to underlying calcified

matrixmatrix Chondrocytes are largest and most syntheticallyChondrocytes are largest and most synthetically

active in this zoneactive in this zone


13/40

Structure ofN

ormal Cartilage Calcified zone:Calcified zone:

Articular cartilage is attached to theArticular cartilage is attached to the

subchondral bone via a thin layer ofsubchondral bone via a thin layer of

calcified cartilagecalcified cartilage

During injury and OA, the mineralizationDuring injury and OA, the mineralization

front advances causing cartilage to thinfront advances causing cartilage to thin


14/40

Structure ofNormal Cartilage


15/40

Structure ofNormal Cartilage


16/40

Normal Cartilage, light micrograph


17/40

Normal Cartilage


18/40

Function of

Normal Cartilage

Critically dependent on composition ofCritically dependent on composition ofECMECM

Type II (IX&XI) provide 3D fibrousType II (IX&XI) provide 3D fibrousnetwork which immobilizes PG and limitsnetwork which immobilizes PG and limitsthe extent of their hydrationthe extent of their hydration

When cartilage compresses H2O andWhen cartilage compresses H2O andsolutes are expressed until repulsive forcessolutes are expressed until repulsive forcesfrom PGs balance load appliedfrom PGs balance load applied


19/40

Function of

Normal Cartilage

On removing load, PGs rehydrate restoringOn removing load, PGs rehydrate restoringshape of cartilageshape of cartilage

Loading and unloading important for theLoading and unloading important for theexchange of proteins in ECM and thus toexchange of proteins in ECM and thus tochondrocyteschondrocytes

Chondrocytes continually replace matrixChondrocytes continually replace matrixmacromolecules lost during normalmacromolecules lost during normalturnoverturnover


20/40

Normal catabolism of cartilage

Chondrocytes secrete degradative proteinasesChondrocytes secrete degradative proteinases

which are responsible for matrix turnoverwhich are responsible for matrix turnover

These include: collagenases (MMPThese include: collagenases (MMP--1), gelatinases1), gelatinases(MMP(MMP--2), stromolysin (MMP2), stromolysin (MMP--3), aggrecanases3), aggrecanases

Normal cartilage metabolism is a highlyNormal cartilage metabolism is a highly

regulated balance between synthesis andregulated balance between synthesis and

degradation of the various matrix componentsdegradation of the various matrix components


21/40

OA cartilage The equilibrium between anabolism andThe equilibrium between anabolism and

catabolism is weighted in favor ofcatabolism is weighted in favor of

degradationdegradation

Disruption of the integrity of the collagenDisruption of the integrity of the collagen

network as occurs early in OA allowsnetwork as occurs early in OA allows

hyperhydration and reduces stiffness ofhyperhydration and reduces stiffness ofcartilagecartilage


22/40

Degenerative cartilage


23/40

Mechanisms responsible for

degradation Catabolism of cartilage results in release ofCatabolism of cartilage results in release of

breakdown products into synovial fluidbreakdown products into synovial fluid

which then initiates an inflammatorywhich then initiates an inflammatoryresponse by synoviocytesresponse by synoviocytes

These antigenic breakdown productsThese antigenic breakdown products

include: chondrointon sulfate, kerataninclude: chondrointon sulfate, keratansulfate, PG fragments, type II collagensulfate, PG fragments, type II collagen

peptides and chondrocyte membranespeptides and chondrocyte membranes


24/40

Mechanisms responsible for

degradation Activated synovial macrophages then recruitActivated synovial macrophages then recruit

PMNs establishing a synovitisPMNs establishing a synovitis

They also release cytokines, proteinases andThey also release cytokines, proteinases andoxygen 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 andThese mediators act on chondrocytes and

synoviocytes modifying synthesis of PGs,synoviocytes modifying synthesis of PGs,

collagen, and hyaluronan as well as promotingcollagen, and hyaluronan as well as promoting

release of catabolic mediatorsrelease of catabolic mediators


25/40

Synovial changes


26/40

Cytokines in OA It is believed that cytokines and growthIt is believed that cytokines and growth

factors play an important role in thefactors play an important role in the

pathophysiology of OApathophysiology of OA ProinflammatoryProinflammatory cytokines are believed tocytokines are believed to

play a pivotal role in the initiation andplay a pivotal role in the initiation anddevelopment of the disease processdevelopment of the disease process

AntiinflammatoryAntiinflammatory cytokines are found incytokines are found inincreased levels in OA synovial fluidincreased levels in OA synovial fluid


27/40

Proinflammatory cytokines TNFTNF-- and IL and IL--1 appear to be the major1 appear to be the major

cytokines involved in OAcytokines involved in OA

Other cytokines involved in OA are: ILOther cytokines involved in OA are: IL--6,6,

ILIL--8, leukemic inhibitory factor (LIF), IL8, leukemic inhibitory factor (LIF), IL--

11, IL11, IL--1717


28/40

TNF

- Formed as propeptide, converted to active form byFormed as propeptide, converted to active form by

TACETACE

Binds to TNFBinds to TNF-- receptor (TNF receptor (TNF--R) on cellR) on cellmembranesmembranes

TACE also cleaves receptor to form solubleTACE also cleaves receptor to form solublereceptor (TNFreceptor (TNF--sR)sR)

At low concentrations TNFAt low concentrations TNF--sR seems to stabilizesR seems to stabilizeTNFTNF-- but at high concentrations it inhibits but at high concentrations it inhibitsactivity by competitive bindingactivity by competitive binding


29/40

IL-1 Formed as inactive precursor, ILFormed as inactive precursor, IL--11 is is

active formactive form

Binds to ILBinds to IL--1 receptor (IL1 receptor (IL--1R), this receptor1R), this receptor

is increased in OA chondrocytesis increased in OA chondrocytes

This receptor may be shed from membraneThis receptor may be shed from membrane

to form ILto form IL--1sR enabling it to compete with1sR enabling it to compete withmembrane associated receptorsmembrane associated receptors


30/40

TNF

- and IL-1 Induce joint articular cells to produce otherInduce joint articular cells to produce other

cytokines such as ILcytokines such as IL--8, IL8, IL--66

They stimulate proteasesThey stimulate proteases They stimulate PGE2 productionThey stimulate PGE2 production

Blocking ILBlocking IL--1 production decreases IL1 production decreases IL--66

and ILand IL--8 but not TNF

8 but not TNF

-- Blocking TNFBlocking TNF-- using antibodies decreased using antibodies decreased

production of ILproduction of IL--1, GM1, GM--CSF and ILCSF and IL--66


31/40

IL-6 Increases number of inflammatory cells inIncreases number of inflammatory cells in

synovial tissuesynovial tissue

Stimulates proliferation of chondrocytesStimulates proliferation of chondrocytes

Induces amplification of ILInduces amplification of IL--1 and thereby1 and thereby

increases MMP production and inhibitsincreases MMP production and inhibits

proteoglycan productionproteoglycan production


32/40

IL-8 Chemotactic for PMNsChemotactic for PMNs

Enhances release of TNFEnhances release of TNF--, IL, IL--1 and IL1 and IL--66


33/40

Leukemic inhibitory factor (LIF

) Enhances ILEnhances IL--1 And IL1 And IL--8 expression in8 expression in

chondrocytes and TNFchondrocytes and TNF-- and IL and IL--1 in1 in

synoviocytessynoviocytes Regulates the metabolism of connectiveRegulates the metabolism of connective

tissue, induces expression of collagenasetissue, induces expression of collagenaseand stromolysinand stromolysin

Stimulates cartilage proteoglycan and NOStimulates cartilage proteoglycan and NOproductionproduction


34/40


35/40

Antiinflammatory cytokines 3 are spontaneously made in synovium and3 are spontaneously made in synovium and

cartilage and increased in OAcartilage and increased in OA

ILIL--4, IL4, IL--10, IL10, IL--1313

Likely the bodys attempt to reduce theLikely the bodys attempt to reduce the

damage being produced bydamage being produced by

proinflammatory cytokines, these twoproinflammatory cytokines, these twoprocesses are not balanced in OAprocesses are not balanced in OA


36/40

IL-4 Decreases ILDecreases IL--11

Decreases TNFDecreases TNF--

Decreases MMPsDecreases MMPs

Increases ILIncreases IL--Ra (competitive inhibitor ofRa (competitive inhibitor ofILIL--1R)1R)

Increases TIMP (tissue inhibitor ofIncreases TIMP (tissue inhibitor ofmetalloproteinases)metalloproteinases)

Inhibits PGE2 releaseInhibits PGE2 release


37/40

IL-1Ra Competitive inhibitor of ILCompetitive inhibitor of IL--1R, not a1R, not a

binding protein of ILbinding protein of IL--1 and it does not1 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


38/40

IL-10, IL-13 ILIL--10 decreases TNF10 decreases TNF-- by increasing by increasing

TNFsRTNFsR

ILIL--13 inhibits many cytokines, increases13 inhibits many cytokines, increases

production of ILproduction of IL--1Ra and blocks IL1Ra and blocks IL--11

productionproduction


39/40

Potential therapeutic applications Neutralization of ILNeutralization of IL--1 and/or TNF1 and/or TNF--

upregulation of MMP gene expressionupregulation of MMP gene expression

ILIL--1Ra suppressed MMP1Ra suppressed MMP--3 transcription in3 transcription in

a rabbit modela rabbit model

Upregulation of antiinflammatory cytokinesUpregulation of antiinflammatory cytokines


40/40

Conclusions Primary etiology of OA remainsPrimary etiology of OA remains

undeterminedundetermined

Believed that cartilage integrity isBelieved that cartilage integrity is

maintained by a balance obtained frommaintained by a balance obtained from

cytokine drivencytokine driven--driven anabolic anddriven anabolic and

catabolic processescatabolic processes

pa tho physiology of osteoarthritis

Documents