Disruption of PTH Receptor 1 in T Cells Protects against PTH-Induced Bone Loss 英文参考文献.docVIP

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Disruption of PTH Receptor 1 in T Cells Protects against PTH-Induced Bone Loss 英文参考文献.doc

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Disruption of PTH Receptor 1 in T Cells Protects against PTH-Induced Bone Loss 英文参考文献

DisruptionofPTHReceptor1inTCellsProtectsagainst PTH-InducedBoneLoss HeshamTawfeek1,BrahmchetnaBedi1,Jau-YiLi1,JonathanAdams1,TatsuyaKobayashi3,M.Neale Weitzmann1,4,HenryM.Kronenberg3,RobertoPacifici1,2* 1DivisionofEndocrinology,MetabolismandLipids,DepartmentofMedicine,EmoryUniversity,Atlanta,Georgia,UnitedStatesofAmerica,2ImmunologyandMolecular PathogenesisProgram,EmoryUniversity,Atlanta,Georgia,UnitedStatesofAmerica,3EndocrineUnit,MassachusettsGeneralHospital,Boston,Massachusetts,United StatesofAmerica,4AtlantaVAMedicalCenter,Decatur,Georgia,UnitedStatesofAmerica Abstract Background:Hyperparathyroidisminhumansandcontinuousparathyroidhormone(cPTH)treatmentinmicecausebone loss by regulating the production of RANKL and OPG by stromal cells (SCs) and osteoblasts (OBs). Recently, it has been reportedthatTcellsarerequiredforcPTHtoinducebonelossasthebindingoftheTcellcostimulatorymoleculeCD40Lto SC receptor CD40 augments SC sensitivity to cPTH. However it is unknown whether direct PTH stimulation of T cells is requiredforcPTHtoinduceboneloss,andwhetherTcellscontributetothebonecatabolicactivityofPTHwithmechanisms otherthaninductionofCD40signalinginSCs. Methodology/PrincipalFindings:HereweshowthatsilencingofPTHreceptor1(PPR)inTcellsblocksthebonelossand the osteoclastic expansion induced by cPTH, thus demonstrating that PPR signaling in T cells is central for PTH-induced reductionofbonemass.MechanisticstudiesrevealedthatPTHactivationoftheTcellPPRstimulatesTcellproductionof theosteoclastogeniccytokinetumornecrosisfactora(TNF).Attestingtotherelevanceofthiseffect,disruptionofTcellTNF productionpreventsPTH-inducedboneloss.WealsoshowthatanovelmechanismbywhichTNFmediatesPTHinduced osteoclastformationisupregulationofCD40expressioninSCs,whichincreasestheirRANKL/OPGproductionratio. Conclusions/Significance:ThesefindingsdemonstratethatPPRsignalinginTcellsplaysanessentialroleinPTHinduced bonelossbypromotingTcellproductionofTNF.ApreviouslyunknowneffectofTNFistoincreaseSCexpressionofCD4