r e v b r a s o r t o p . 2013;48(6):471–474
w w w . r b o . o r g . b r
Update
Article
Is
osteoarthritis
a
mechanical
or
inflammatory
disease?
夽
,
夽夽
Márcia
Uchôa
de
Rezende
∗,
Gustavo
Constantino
de
Campos
InstituteofOrthopedicsandTraumatology,HospitaldasClínicas,SchoolofMedicine,UniversityofSãoPaulo,SãoPaulo,SP,Brazil
a
r
t
i
c
l
e
i
n
f
o
Articlehistory:
Received14March2013 Accepted19March2013
Keywords:
Osteoarthritis Inflammation Arthritis Chronicdisease Mechanics
a
b
s
t
r
a
c
t
Traditionally considered “wear and tear” disease, the pathogenic mechanisms of osteoarthritis have notyet beenelucidated.The increasingnumber ofarticles demon-stratingtheinfluenceofinflammatoryfactorsintheonsetandprogressionofthedisease currently raisesgreatdebateintheliteratureabout theimportanceofeachofthe fac-tors involved in the disease. Even the choice betweenthe terms “Osteoarthritis” and “Osteoarthrosis”generatescontroversy,sincethefirsttermimpliesthepresenceof inflam-mationasthekeygeneratorofthedisease,andthelatterdenotesadegenerative/mechanical causalfactor.Theaimofthisrevisionarticleistopromoteadebateontheinfluenceof inflammatoryfactorsandmechanicalfactorsinthepathogenesisofOA.
©2013SociedadeBrasileiradeOrtopediaeTraumatologia.PublishedbyElsevierEditora Ltda.Allrightsreserved.
A
osteoartrite
é
uma
doenc¸a
mecânica
ou
inflamatória?
Palavras-chave:
Osteoartrite Inflamac¸ão Artrite Doenc¸acrônica Mecânica
r
e
s
u
m
o
Classicamenteconsideradaumadoenc¸adewearandtear(desgaste),aosteoartriteainda nãotemelucidadostodososseusmecanismospatogênicos.Ocrescentenúmerodeartigos quedemonstramainfluênciadosfatoresinflamatóriosnosurgimentoenaevoluc¸ãoda doenc¸asuscita,atualmente,grandedebatenaliteraturasobreaimportânciadecadaum dosfatoresenvolvidos.Atémesmoaescolhadostermososteoartriteeosteoartrosegera polêmica,umavezqueoprimeiroimplicaapresenc¸adainflamac¸ãocomofatorprimordial geradordadoenc¸aeoúltimodenotaumfatorcausaldegenerativo/mecânico.Oobjetivo desteartigoépromoverumdebatesobreainfluênciadosfatoresinflamatóriosedosfatores mecânicosnapatogênesedaOA.
©2013SociedadeBrasileiradeOrtopediaeTraumatologia.PublicadoporElsevierEditora Ltda.Todososdireitosreservados.
夽
Pleasecitethisarticleas:deRezendeMU,deCamposGC.Aosteoartriteéumadoenc¸amecânicaouinflamatória?RevBrasOrtop. 2013;48:471–474.
夽夽
WorkperformedattheInstituteofOrthopedicsandTraumatology,FacultyofMedicine,UniversityofSãoPaulo,SãoPaulo,SP,Brazil.
∗ Correspondingauthor.
E-mail:murezende@uol.com.br(M.U.deRezende).
2255-4971/$–seefrontmatter©2013SociedadeBrasileiradeOrtopediaeTraumatologia.PublishedbyElsevierEditoraLtda.Allrightsreserved.
472
rev bras ortop.2013;48(6):471–474Introduction
Theconceptthatosteoarthritis(OA)isaninevitable conse-quenceofaging,i.e.wearandtearonthejointsduetouse,is graduallybeingleftbehind.Theterm“degenerativejoint dis-ease”,whichisstillgreatlyused,denotestheideaoffutility andinevitabilityanddoesnotexpressthetruecomplexityof theproblem.Inviewofthecurrentknowledge,twosetsof fac-torsthatseemtoplayafundamentalroleinthedevelopment ofOAhavearisen:mechanicalandinflammatoryfactors. How-ever,therearedivergentviewsintheliteratureregardingthe importancetobegiventoeachofthese.Theaimofthis arti-clewastopromoteadebateontheinfluenceofinflammatory factorsandmechanicalfactorsonthepathogenesisofOA.
Takingtheroleof“devil’sadvocate”,wefirstlytryto con-vincereadersthatOAisaninflammatorydisease.Wethen presentargumentsinfavoroftreatingitasamechanical dis-ease.Weinvitereaders,beforestartingtoreadonwards,to choosejustoneofthesetheories.Attheend,webelievethat somereaderswillsurprisethemselvesbychangingtheir opin-ionafterseeingthestrongargumentsonbothsides.
Osteoarthritis
is
an
inflammatory
disease
The inflammatory process found in OA has been studied forseveral decades.1,2 According tosomerecent studies,3,4
OA behaves like an autoinflammatory disease, caused by responsesmediatedbychondrocytesandsynoviocytes.The serum and synovial levels of inflammatory cytokines are higherinpatientswithOA.5,6Thereismuchclinicalevidence
ofthe importanceof inflammationin the pathogenesis of thedisease,whichevenprovidesnewpotentialtherapeutic targets.7
AmongtheclinicalsignsseeninOAinanypartofthebody, thereisanincreaseinjointvolume,probablyduetosynovial effusionorthickening.Thisisanirrefutablesignofthe pres-ence ofsynovitis.There are increasingnumbers ofstudies intheliteraturecorrelatingsynovitiswithOA.Inasearchin PubMedusingthetermsosteoarthritisandsynovitis,wefound 1253publishedpaperswiththisassociation.PatientswithOA frequentlypresentepisodesinwhichtheconditionbecomes acute,knownasflare-ups,whichfollowacoursethatincludes jointeffusion,painwhenrestingand/ormorningstiffness.
Magneticresonanceimaging(MRI)withcontrastand ultra-sonography (US) are valid and efficient tools for studying synovitis.8Synovitisandjointeffusionincreasetheriskofloss
ofcartilageinkneesthatinitiallydonothaveOA.9Bymeans
ofarthroscopy, Ayral et al.10 observedthat the greater the
degreeofsynovitisencounteredwas,thegreaterthechanceof jointdeteriorationwouldbe.Inanotherstudy,greatpresence ofinflamedtissuewasobservedinhistologicalsectionsfrom osteoarthriticjoints.11
In an experimental model for OA caused by means of collagenase-induced lesions,12 the group in which the
macrophagesofthesynoviumweredepletedbeforeOAwas induced did not present degradation. This signifies that macrophageshaveafundamentalroleinthepathogenesisof OAandarenotjustaconsequenceofit.Thestressmechanism
itselfoftenfunctionslikeaveritablecytokine.13 Mechanical
stressispickedupandinterpretedbymechanicalreceptors, which then activate inflammatorycascades, exactlyin the samewayasoccursinactivationcausedbycytokines.14
AmongpatientswithOA,aphenotypeinwhichthe dis-ease accompanies metabolic disorders suchas diabetes or obesity15,16 clearly exists. Adipose tissueiscapableof
pro-ducingadipokinesandotherinflammatorymediators,which increasethe levelsofinflammatoryactivitythroughoutthe body,17 and even in osteoarthritic joints.18 Obese patients
presenttwiceasmuchriskofpresentingOAintheirhands, whichsignifiesthatthegreaterincidenceofOAintheknees andhipsofobeseindividualscannotbeattributedonlytotheir greaterweight.19
Finally, it is known that aging increases the cellular responsetoinflammatoryfactors.20Cellsenescenceincreases
cytokineproductionandthusagingcausesastateofchronic inflammation that is characterized as low-intensity, sys-temic and subclinical. To describe this state, Franceschi etal.introducedtheterminflammaging,21asacombination
betweeninflammationandaging.
Osteoarthritis
is
a
mechanical
disease
Sayingthatadiseaseismechanicalmeansthatitisrelated tomovementandphysicalforces,oriscausedbythese.This ispreciselywhatleadstoOA,i.e.increasedphysicalforcein localizedareas ofajoint.OAisajoint’spathophysiological responsetoamechanicalinjury.22Itrepresentsanattempt
by thejoint tocorrect anabnormalmechanical stress and repairtheinjuryresultingfromthis.Althoughsomeauthors considerthatincreasedlevelsofcytokines,freeradicalsand degradative enzymes inthe jointare the cause ofOA,2–4,16
there is evidence indicating that in fact all inflammatory responsesaretheresultofattemptstorepairosteoarthritic joints.23
Amongthecausesthatmayleadtoanabnormalincrease inforcesinlocalizedareasofthejoint,thefollowingcanbe observed:(1)congenitaloracquiredabnormalanatomy,such ascongenitalmisalignmentorameniscaloranteriorcruciate ligamentinjury,whichleadstoincreasedstressevenunder physiologicalloads;(2)excessiveloading,likeinobese indi-viduals;(3)acombinationoffactors,whichisthecommonest scenario.Moreover,itisnotthemisalignmentthatcausesOA, butitseffectofconcentratingtheintra-articularstress.Itis nottheestrogendeficiencyorageneticabnormalityinitself, but theeffects thatstemfrom thesealterationsthat cause thejointtissuestolosetheabilitytoprotectthemselves ade-quatelyagainstloadsthatareoftenphysiological.
AbnormalmechanicscauseOA.Mostanimalmodelsuse focused load increases to cause OA (meniscal injury or resection of the ACL).24 Wu et al.25 caused OA in rabbits
through inducingmisalignment with an increase in varus moment.Animalmodelsthatdonotcauseinjury(for exam-ple,usingiodineacetate)donotresembleOA.Thereareno modelswithcytokinesorinflammatoryfactors.
Inhumans,manystudieshavecorrelatedmeniscalinjuries withOA.26 Occasionalmeniscalinjuriesoccurin30–60%of
rev bras ortop.2013;48(6):471–474
473
increasetheriskofdevelopingOA tenfold.28 Moisioet al.29
clearlydemonstratedthatmeniscalinjuriesprecedecartilage losses,throughfindingthattherewasgreaterriskonlyof pos-teriorcartilagelossinposteriormeniscaltears,andgreater risk of cartilage loss only in regions adjacent to meniscal bodylesions.Surgerytoremovemeniscalinjuries(evenpartial removalofmenisci)increasesthefocalstressonthecartilage andcauseshighratesofOA.26Becauseofthehighprevalence
ofmeniscalinjuries,bothinyoungandinolderindividuals, thesecanbeconsideredtoberesponsiblefor40–50%ofthe casesofOAoftheknees.
Misalignment causes OA.30 Congenital hip dysplasia
increasestheriskofdevelopingOAby2.8-fold.31Varus
align-mentofthekneedysplasiaincreasestheriskofdeveloping OAinthemedicalcompartmentbyaround3.5-fold.30Knees
invarusalignmentgiverisetobonemarrowinjuriesinthe medialcompartment,whilevalguskneesgiverisetoinjuries inthelateralcompartment.32Anexternaladductormoment
inthekneecreatesaviciouscircleofvarus,inthatthegreater thevarusis,thegreater theadductormomentwillbe.This increasestheloadinthemedialcompartmentandleadsto evengreatervarus,aswellasreleasingdebrisinthejointand inthebonemarrowinjuries.Interestingly,thereisno inflam-mationinthebonemarrowinjuriesfoundincasesofOA.33
Thereislittleedema,withmuchfibrosisandbonenecrosis, andthese characteristicsshow thatthe injuriesareinfact fracturesduetoinsufficiency.Oncetheabnormalmechanics havedeveloped,theyoverwhelmallotherfactors.Therefore, themechanicsneedtobetreated,andtheproofofthisisthe long-lastingsuccessoftreatmentbymeansofvarus-reducing osteotomyoftheknee.34Whenthisiscorrectlyindicated,it
canbringanimprovementinsymptomsthatlastsformany years,incontrastwiththetransitoryeffect,withoutcentral actiononthepathogenesisofOA,thatisseenintreatments thatfocusontheinflammation,suchasintra-articular injec-tionofcorticosteroids.35
InrelationtoriskfactorsfordevelopingOA:(1)obesity cer-tainlyincreasestheloadonthejoint;(2)greaterageprobably leavesthekneemorevulnerabletoinjurythroughavarietyof factors,suchasdiminishedmusclestrength,forexample;(3) occupationalfactors giverise tooverloadonspecificjoints, relating to the individual’s occupation; and (4) the genetic influencefordevelopmentofradiographicOAalsorelatesto specificlocalities,i.e.familiesinheritOAoftheknees,OAof thehandsorOAofthehips.Thus,geneticinheritanceofOA doesnotoccursystematically,ashadbeenthought. General-izedOAisnotinheritedbut,rather,OSofaspecificjoint.36This
maymeanthat,inreality,theinheritancecomprisesphysical characteristicsofaparticularjoint,whichwillleadto mechan-icaldisorders thatcauseOA.Noneoftheseriskfactorsare related toinflammation. C-reactive protein(CRP), which is themostimportantoftheinflammatorymarkers,does not presentanycorrelationwithOA.37
Final
remarks
The international community is still absolutely divided regardingtheexactmechanismofthisdisease.Theanswers toquestionsaboutthephysiopathologicalmechanismsand
factorsinvolvedindiseaseprogressionandtreatmentofOA unfortunatelyremainnebulous.Thisisacomplex pathologi-calconditionresultingfrominteractionsofavarietyofcauses andfactors.Consideringtheproblemtobepurely mechani-calorpurelyinflammatoryseemstobeanattempttosimplify somethingthatisnotsimple.
The fundamental concept isthat this isa failure ofan entirejoint,i.e.acompleteorganthatiscomposednotonlyof cartilagebutalsoofvarioustissuessuchasthesynovium, sub-chondralbone,capsule,menisci,musclesandtendons.The therapyshouldthereforebeholisticandencompassawide diversityofaspectsofthedisease.Thereisstillaneedfor greateramountsofinformationthanwhatiscurrently avail-able,foranyattempttoreachadefinitiveconclusiononthis matter.
Conflicts
of
interest
Theauthorsdeclarenoconflictsofinterest.
r
e
f
e
r
e
n
c
e
s
1.DieppeP.Inflammationinosteoarthritis.RheumatolRehabil.
1978;Suppl.:59–63.
2.PincusT.Clinicalevidenceforosteoarthritisasan
inflammatorydisease.CurrRheumatolRep.2001;3(6):524–34.
3.KonttinenYT,SillatT,BarretoG,AinolaM,NordstromDC.
Osteoarthritisasanautoinflammatorydiseasecausedby
chondrocyte-mediatedinflammatoryresponses.Arthritis
Rheum.2012;64(3):613–6.
4.BonnetCS,WalshDA.Osteoarthritis,angiogenesis,and
inflammation.Rheumatology(Oxford).2005;44(1):7–16.
5.SohnDH,SokoloveJ,SharpeO,ErhartJC,ChandraPE,Lahey
LJ,etal.Plasmaproteinspresentinosteoarthriticsynovial
fluidcanstimulatecytokineproductionviaToll-likereceptor
4.ArthritisResTher.2012;14(1):R7.
6.PearleAD,ScanzelloCR,GeorgeS,MandlLA,DiCarloEF,
PetersonM,etal.Elevatedhigh-sensitivityC-reactiveprotein
levelsareassociatedwithlocalinflammatoryfindingsin
patientswithosteoarthritis.OsteoarthritisCartilage.
2007;15(5):516–23.
7.PelletierJP,Martel-PelletierJ,AbramsonSB.Osteoarthritis,an
inflammatorydisease:potentialimplicationfortheselection
ofnewtherapeutictargets.ArthritisRheum.
2001;44(6):1237–47.
8.GuermaziA,RoemerFW,HayashiD.Imagingof
osteoarthritis:updatefromaradiologicalperspective.Curr
OpinRheumatol.2011;23(5):484–91.
9.RoemerFW,GuermaziA,FelsonDT,NiuJ,NevittMC,Crema
MD,etal.PresenceofMRI-detectedjointeffusionand
synovitisincreasestheriskofcartilagelossinkneeswithout
osteoarthritisat30-monthfollow-up:theMOSTstudy.Ann
RheumDis.2011;70(10):1804–9.
10.AyralX,PickeringEH,WoodworthTG,MackillopN,Dougados
M.Synovitis:apotentialpredictivefactorofstructural
progressionofmedialtibiofemoralknee
osteoarthritis—resultsofa1yearlongitudinalarthroscopic
studyin422patients.OsteoarthritisCartilage.
2005;13(5):361–7.
11.YoungL,KatribA,CuelloC,Vollmer-ConnaU,BertouchJV,
Roberts-ThomsonPJ,etal.Effectsofintraarticular
glucocorticoidsonmacrophageinfiltrationandmediatorsof
474
rev bras ortop.2013;48(6):471–474inadouble-blind,placebo-controlledstudy.ArthritisRheum.
2001;44(2):343–50.
12.BlomAB,vanLentPL,LibregtsS,HolthuysenAE,vander
KraanPM,vanRooijenN,etal.Crucialroleof
macrophagesinmatrixmetalloproteinase-mediatedcartilage
destructionduringexperimentalosteoarthritis:involvement
ofmatrixmetalloproteinase3.ArthritisRheum.
2007;56(1):147–57.
13.KawakitaK,NishiyamaT,FujishiroT,HayashiS,KanzakiN,
HashimotoS,etal.Aktphosphorylationinhuman
chondrocytesisregulatedbyp53R2inresponsetomechanical
stress.OsteoarthritisCartilage.2012;20(12):1603–9.
14.PiscoyaJL,FermorB,KrausVB,StablerTV,GuilakF.The
influenceofmechanicalcompressionontheinductionof
osteoarthritis-relatedbiomarkersinarticularcartilage
explants.OsteoarthritisCartilage.2005;13(12):1092–9.
15.ZhuoQ,YangW,ChenJ,WangY.Metabolicsyndromemeets
osteoarthritis.NatRevRheumatol.2012;8(12):729–37.
16.BerenbaumF.Diabetes-inducedosteoarthritis:fromanew
paradigmtoanewphenotype.PostgradMedJ.
2012;88(1038):240–2.
17.OsbornO,OlefskyJM.Thecellularandsignalingnetworks
linkingtheimmunesystemandmetabolismindisease.Nat
Med.2012;18(3):363–74.
18.SowersMR,Karvonen-GutierrezCA.Theevolvingroleof
obesityinkneeosteoarthritis.CurrOpinRheumatol.
2010;22(5):533–7.
19.YusufE.Metabolicfactorsinosteoarthritis:obesepeopledo
notwalkontheirhands.ArthritisResTher.2012;14(4):123.
20.ForsythCB,ColeA,MurphyG,BieniasJL,ImHJ,LoeserJrRF.
Increasedmatrixmetalloproteinase-13productionwithaging
byhumanarticularchondrocytesinresponsetocatabolic
stimuli.JGerontolABiolSciMedSci.2005;60(9):
1118–24.
21.FranceschiC,BonafeM,ValensinS,OlivieriF,DeLucaM,
OttavianiE,etal.Inflammaging.Anevolutionaryperspective
onimmunosenescence.AnnNYAcadSci.2000;908:244–54.
22.BrandtKD,DieppeP,RadinE.Etiopathogenesisof
osteoarthritis.MedClinNorthAm.2009;93(1):1–24.
23.BrandtKD,DieppeP,RadinEL.Commentary:isitusefulto
subset“primary”osteoarthritis?Acritiquebasedonevidence
regardingtheetiopathogenesisofosteoarthritis.Semin
ArthritisRheum.2009;39(2):81–95.
24.PapaioannouN,KrallisN,TriantafillopoulosI,KhaldiL,
DontasI,LyritisG.Optimaltimingofresearchafteranterior
cruciateligamentresectioninrabbits.ContempTopLab
AnimSci.2004;43(6):22–7.
25.WuDD,BurrDB,BoydRD,RadinEL.Boneandcartilage
changesfollowingexperimentalvarusorvalgustibial
angulation.JOrthopRes.1990;8(4):572–85.
26.PapaliaR,DelBuonoA,OstiL,DenaroV,MaffulliN.
Meniscectomyasariskfactorforkneeosteoarthritis:a
systematicreview.BrMedBull.2011;99:89–106.
27.EnglundM,GuermaziA,GaleD,HunterDJ,AliabadiP,Clancy
M,etal.IncidentalmeniscalfindingsonkneeMRIin
middle-agedandelderlypersons.NEnglJMed.
2008;359(11):1108–15.
28.EnglundM,GuermaziA,RoemerFW,AliabadiP,YangM,
LewisCE,etal.Meniscaltearinkneeswithoutsurgeryand
thedevelopmentofradiographicosteoarthritisamong
middle-agedandelderlypersons:theMulticenter
OsteoarthritisStudy.ArthritisRheum.2009;60(3):831–9.
29.MoisioK,ChangA,EcksteinF,ChmielJS,WirthW,AlmagorO,
etal.Varus-valgusalignment:reducedriskofsubsequent
cartilagelossinthelessloadedcompartment.Arthritis
Rheum.2011;63(4):1002–9.
30.HayashiD,EnglundM,RoemerFW,NiuJ,SharmaL,Felson
DT,etal.Kneemalalignmentisassociatedwithanincreased
riskforincidentandenlargingbonemarrowlesionsinthe
moreloadedcompartments:theMOSTstudy.Osteoarthritis
Cartilage.2012;20(11):1227–33.
31.LaneNE,LinP,ChristiansenL,GoreLR,WilliamsEN,
HochbergMC,etal.Associationofmildacetabulardysplasia
withanincreasedriskofincidenthiposteoarthritisinelderly
whitewomen:thestudyofosteoporoticfractures.Arthritis
Rheum.2000;43(2):400–4.
32.FelsonDT,McLaughlinS,GogginsJ,LaValleyMP,GaleME,
TottermanS,etal.Bonemarrowedemaanditsrelationto
progressionofkneeosteoarthritis.AnnInternMed.2003;
139(5Pt1):330–6.
33.TaljanovicMS,GrahamAR,BenjaminJB,GmitroAF,Krupinski
EA,SchwartzSA,etal.Bonemarrowedemapatternin
advancedhiposteoarthritis:quantitativeassessmentwith
magneticresonanceimagingandcorrelationwithclinical
examination,radiographicfindings,andhistopathology.
SkeletalRadiol.2008;37(5):423–31.
34.BrouwerRW,JakmaTS,Bierma-ZeinstraSM,VerhagenAP,
VerhaarJ.Osteotomyfortreatingkneeosteoarthritis.
CochraneDatabaseSystRev.2005;1:CD190040.
35.BellamyN,CampbellJ,RobinsonV,GeeT,BourneR,WellsG.
Intraarticularcorticosteroidfortreatmentofosteoarthritisof
theknee.CochraneDatabaseSystRev.2006;2:CD280053.
36.MacGregorAJ,LiQ,SpectorTD,WilliamsFM.Thegenetic
influenceonradiographicosteoarthritisissitespecificatthe
hand,hipandknee.Rheumatology(Oxford).
2009;48(3):277–80.
37.VladSC,NeogiT,AliabadiP,FontesJD,FelsonDT.No
associationbetweenmarkersofinflammationand
osteoarthritisofthehandsandknees.JRheumatol.
