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Study Design: TheinteractionbetweenMacrophageinhibitionfactor(MIF)anditsreceptorCD74modulatedtheinflammatoryactivityand matrixmetabolisminhumandegeneratedcartilageendplate(CEP)viaextracellularsignal-regulatedkinase(ERK)signaling pathway.Anabolic/catabolicfactorsinpathogenesisofCEPdegenerationwereevaluated. Objective: TostudytheroleofERKpathwayinCEPchondrocytesresponsetoMIF-CD74signal. Background: MIF-CD74signaliscloselyrelatedtotheCEPdegenerationbyinducingthesecretionofinflammatorycytokines.ERK-mediated inflammatorypathwayplaysacrucialroleintheintervertebraldisc(IVD)degeneration.However,theroleoftheERKpathwayin CEPchondrocytesresponsetoMIF-CD74signalhasnotbeenfullyelucidated. Methods: HumandegeneratedCEPchondrocyteswereexposedtoMIF,withorwithoutERKinhibition;CD74knockoutandrestoration chondrocyteswerealsoexposedtoMIF,withorwithoutERKinhibition.mRNAwereisolatedforrealtimepolymerasechain reactionmeasurementofgeneexpression.Westernblottingwascarriedouttoanalyzetheproteinexpressionpatterns. Results: ERKexpressionwassignificantlyincreasedbyMIFanddecreasedbyitsinhibitorPD98059.Inflammatorycytokinesexpressionwas significantlyincreasedbyMIF-inducedERKactivationandsignificantlysuppressedbyPD98059.Onthecontrary,matrix expressionwassignificantlydecreasedbyMIF-inducedERKactivationandreversedbyPD98059.PD98059hadnosignificant effectonERKexpressionofCD74knockoutchondrocytesbutdecreasedERKexpressioninCD74-restoredchondrocytes. Anabolic/catabolicfactorswasnotsignificantlyaffectedbytheMIFinCD74knockoutchondrocytes.Inflammatorycytokines expressionwassignificantlyincreasedandmatrixexpressionwasdecreasedinCD74-restoredchondrocytes. Conclusion: TheseresultsshowthatMIF-CD74signalelicitsanimbalancebetweenanabolicandcatabolicmetabolisminCEPchondrocytes viaERKsignalpathway.ERKinhibitioncouldexerttherapeuticeffectagainsttheharmfuleffectsofMIF-CD74signal.