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Enhanced Osteoclastic Resorption and Responsiveness to Mechanical Load in Gap Junction Deficient Bone 英文参考文献.docVIP

Enhanced Osteoclastic Resorption and Responsiveness to Mechanical Load in Gap Junction Deficient Bone 英文参考文献.doc

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Enhanced Osteoclastic Resorption and Responsiveness to Mechanical Load in Gap Junction Deficient Bone 英文参考文献

EnhancedOsteoclasticResorptionandResponsiveness toMechanicalLoadinGapJunctionDeficientBone YueZhang1,EmmanuelM.Paul1,VikramSathyendra1,AndrewDavison1,NeilSharkey1,SarahBronson2, SundarSrinivasan3,TedS.Gross3,HenryJ.Donahue1,2* 1DivisionofMusculoskeletalSciences,DepartmentofOrthopaedicsandRehabilitation,PennStateCollegeofMedicine,Hershey,Pennsylvania,UnitedStatesofAmerica, 2Department ofCellular and Molecular Physiology, PennState College ofMedicine, Hershey, Pennsylvania, United States ofAmerica, 3Department of Orthopaedics, UniversityofWashington,Seattle,Washington,UnitedStatesofAmerica Abstract Emerging evidence suggests that connexin mediated gap junctional intercellular communication contributes to many aspectsofbonebiologyincludingbonedevelopment,maintenanceofbonehomeostasisandresponsivenessofbonecells todiverseextracellularsignals.Deletionofconnexin43,thepredominantgapjunctionproteininbone,isembryoniclethal makingitchallengingtoexaminetheroleofconnexin43inboneinvivo.However,transgenicmurinemodelsinwhichonly osteocytes and osteoblasts are deficient in connexin 43, and which are fully viable, have recently been developed. Unfortunately,thebonephenotypeofdifferentconnexin43deficientmodelshasbeenvariable.Toaddressthisissue,we used anosteocalcin driven Cre-loxsystem tocreateosteoblast andosteocyte specificconnexin 43 deficientmice. These micedisplayedbonelossasaresultofincreasedboneresorptionandosteoclastogenesis.Themechanismunderlyingthis increasedosteoclastogenesisincludedincreasesintheosteocytic,butnotosteoblastic,RANKL/OPGratio.Previousinvitro studies suggest that connexin 43 deficient bone cells are less responsive to biomechanical signals. Interestingly, and in contrast to in vitro studies, we found that connexin 43 deficient mice displayed an enhanced anabolic response to mechanical load. Our results suggest that transient inhibition of connexin 43 expression and gap junctional intercellular communication may prove a potentially powerful means of enhancin

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