Fibroblast growth factor receptor 1 is principally responsible for fibroblast growth factor 2-induced catabolic activities in human articular chondrocytes.docVIP

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Fibroblast growth factor receptor 1 is principally responsible for fibroblast growth factor 2-induced catabolic activities in human articular chondrocytes.doc

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Fibroblast growth factor receptor 1 is principally responsible for fibroblast growth factor 2-induced catabolic activities in human articular chondrocytes

Yanetal.ArthritisResearchTherapy2011,13:R130 /content/13/4/R130 RESEARCH ARTICLE OpenAccess Fibroblastgrowthfactorreceptor1isprincipally responsibleforfibroblastgrowthfactor2-induced catabolicactivitiesinhumanarticular chondrocytes DongyaoYan1,DiChen1,SimonMCool5,6,AndreJvanWijnen6,7,KatalinMikecz3,GillianMurphy8and Hee-JeongIm1,2,3,4* Abstract Introduction:Cartilagedegenerationdrivenbycatabolicstimuliisacriticalpathophysiologicalprocessin osteoarthritis(OA).Wehavedefinedfibroblastgrowthfactor2(FGF-2)asadegenerativemediatorinadulthuman articularchondrocytes.BiologicaleffectsmediatedbyFGF-2includeinhibitionofproteoglycanproduction,up- regulationofmatrixmetalloproteinase-13(MMP-13),andstimulationofothercatabolicfactors.Inthisstudy,we identifiedthespecificreceptorresponsibleforthecatabolicfunctionsofFGF-2,andestablisheda pathophysiologicalconnectionbetweentheFGF-2receptorandOA. Methods:Primaryhumanarticularchondrocyteswereculturedinmonolayer(24hours)oralginatebeads(21 days),andstimulatedwithFGF-2orFGF18,inthepresenceorabsenceofFGFR1(FGFreceptor1)inhibitor. Proteoglycanaccumulationandchondrocyteproliferationwereassessedbydimethylmethyleneblue(DMMB)assay andDNAassay,respectively.ExpressionofFGFRs(FGFR1toFGFR4)wasassessedbyflowcytometry, immunoblotting,andquantitativereal-timePCR(qPCR).ThedistinctiverolesofFGFR1andFGFR3afterstimulation withFGF-2wereevaluatedusingeitherpharmacologicalinhibitorsorFGFRsmallinterferingRNA(siRNA).Luciferase reportergeneassayswereusedtoquantifytheeffectsofFGF-2andFGFR1inhibitoronMMP-13promoteractivity. Results:ChondrocyteproliferationwassignificantlyenhancedinthepresenceofFGF-2stimulation,whichwas inhibitedbythepharmacologicalinhibitorofFGFR1.Proteoglycanaccumulationwasreducedby50%inthe presenceofFGF-2,andthisreductionwassuccessfullyrescuedbyFGFR1inhibitor.FGFR1inhibitorsalsofully reversedtheup-regulationofMMP-13expressionandpromoteractivitystimulatedbyFGF-2.BlockadeofFGFR1 signalingbyeitherchemicalinhibitorsorsiRNAtargetingFGFR1ratherthanFG