integrin-review-整合素受体信号通路综述

13RheumatolIntDOI10.1007/s00296-014-3137-5REVIEWARTICLE-PATHOLOGYREVIEWRoleofintegrinsandtheirligandsinosteoarthriticcartilageJianTian·Fang‑JieZhang·Guang‑HuaLeiReceived:25May2014/Accepted:17September2014©Springer-VerlagBerlinHeidelberg2014[1].RadiographicevidenceofOAoccursinthemajorityofpeopleby65yearsofage,andamongthemabout80%inpeoplewhoagedover75years[2].However,thepathogen-esisofthisdiseaseisnotfullyelucidated.CartilagedamageisoneofthemajorpathologicalchangesinOA.Articularcartilageisanavascular,aneu-ral,alymphatic,andviscoelasticconnectivetissuethatfunctionsautonomouslytobearloadsandprovidealmostfriction-freemovementofdiarthrodialjoints[3].Chondro-cytes,theonlycellpopulationofadultarticularcartilage,arestronglyinvolvedinmaintainingthedynamicequi-libriumbetweensynthesisanddegradationoftheextra-cellularmatrix(ECM)[4].Collagensrepresentthemajorstructuralcomponentsofthearticularcartilage.CartilageismadeupoftwomainECMmacromolecules:typeIIcollagenandaggrecan,alargeaggregatingproteoglycan[5,6].Cartilagedestructionisthoughttobemediatedbytwomainenzymefamilies:thematrixmetalloproteinases(MMPs)areresponsibleforthecartilagecollagenbreak-down,whereasenzymesfromdisintegrinandmetallopro-teinasedomainwiththrombospondinmotifs(ADAMTS)familymediatecartilageaggrecanloss[7].Activationofbiochemicalpathwaysinvolvestheproductionofproin-flammatorycytokines,inflammation,degradationoftheECMbyMMPsandADAMTS,andcessationofECMsyn-thesisviadedifferentiationandapoptosisofchondrocytes[8,9].Therefore,theECMisavitalcellularenvironment,andinteractionsbetweenthecellandECMareimportantinregulatingmanybiologicalprocesses,whichincludecellgrowth,differentiation,andsurvival[10,11].Cell–matrixinteractionscontrolcellfunctionandbehav-iorbysignaltransductionthroughavarietyofcellsur-facereceptors.TheintegrinsarethemajorfamilyofECMreceptors,whichcantransmitinformationfromthematrixtothecell.IntegrinbindingofECMligandsresultsintheAbstractOsteoarthritis(OA)isadegenerativedisease,whichischaracterizedbyarticularcartilagedestruction,andmainlyaffectstheolderpeople.Theextracellularmatrix(ECM)providesavitalcellularenvironment,andinteractionsbetweenthecellandECMareimportantinreg-ulatingmanybiologicalprocesses,includingcellgrowth,differentiation,andsurvival.However,thepathogenesisofthisdiseaseisnotfullyelucidated,anditcannotbecuredtotally.Integrinsareoneofthemajorreceptorsinchondro-cytes.Anumberofstudiesconfirmedthatthechondrocytesexpressseveralintegrinsincludingα5β1,αVβ3,αVβ5,α6β1,α1β1,α2β1,α10β1,andα3β1,andsomeintegrinsligandsmightactastheOAprogressionbiomarkers.ThisreviewfocusesonthefunctionalroleofintegrinsandtheirextracellularligandsinOAprogression,especiallyOAcar-tilage.ClearunderstandingoftheroleofintegrinsandtheirligandsinOAcartilagemayhaveimpactonfuturedevelop-mentofsuccessfultherapeuticapproachestoOA.KeywordsChondrocyte·Integrin·Fibronectin·TenascinC·Osteopontin·Osteoarthritis·CartilageIntroductionOsteoarthritis(OA)isadegenerativediseaseandischar-acterizedbyarticularcartilagedestructionalongwithchangesoccurringinotherjointcomponentsincludingbone,menisci,synovium,ligaments,capsule,andmusclesRheumatologyINTERNATIONALJ.Tian·F.-J.Zhang·G.-H.Lei(*)DepartmentofOrthopaedics,XiangyaHospital,CentralSouthUniversity,No.87XiangyaRoad,Changsha410008,Hunan,Chinae-mail:[e-mail];[e-mail]13formationofsignalingcomplexes,whichplayakeyroleintheregulationofcellsurvival,adhesion,proliferation,dif-ferentiation,andmatrixremodeling[11,12].TodevelopnewandsuccessfulapproachesforthetreatmentforOA,itisessentialtoelucidatetheroleofintegrinsandtheirligandsinthepathogenesisofOA.Inthisstudy,wehavereviewedtheroleofintegrinsandtheirligandsontheOAcartilage,consequentlywhichcontributestoOAprogression.IntegrinsstructureandfunctionThefirstintegrinwasidentifiedalmost30yearsago;“integrin”wasnamedforthisproteincomplexbecauseofitsroleasanintegralmembranecomplexinvolvedinthetransmembraneassociationbetweentheECMandthecytoskeleton[13].ThefirstintegrinofwhichcDNAwassequencedencodesapolypeptideof89kD,withthepres-enceofalargeN-terminalextracellulardomain,asingletransmembranesegment,andasmallC-terminalcytoplas-micdomain.Theextracellulardomaincontainsathreefoldrepeatofanovel40residuecysteine-richsegment,andthecytoplasmicdomaincontainsatyrosineresiduethatisapotentialsiteforphosphorylationbytyrosinekinases[13].Sofar,itiswellknownasafamilyofheterodimerictrans-membranereceptorsconsistingofanαandaβsubunit,whicheachhavealargeectodomain,asingletransmem-branedomain,andagenerallyshortcytoplasmictail.Allofthedifferent18αand8βsubunitsareknowninhumans,whichcanbecombinedto24differentintegrinreceptors[14,15].Multipleαsubunitscancombinewithsingleβsubunits(andviceversa),givingriseto“combinatorial”ligandspecificity,asshowninFig.1.The24knownintegrinheterodimerscanbeclassifiedasarginine–glycine–aspartate(RGD)-binding,theα4family,leukocyteadhesionintegrins,laminin-binding,andI-domaincollagen-binding,asshownintheTable1.Alloftheseinteg-rinscanbefurthersegregatedintotwogroups,eithercontain-ingor