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