title: Enhanced osteoclastic resorption and responsiveness to mechanical load in gap junction deficient bone.
abstract: Emerging evidence suggests that connexin mediated gap junctional intercellular communication contributes to many aspects of bone biology including bone development, maintenance of bone homeostasis and responsiveness of bone cells to diverse extracellular signals. Deletion of connexin 43, the predominant gap junction protein in bone, is embryonic lethal making it challenging to examine the role of connexin 43 in bone in vivo. However, transgenic murine models in which only osteocytes and osteoblasts are deficient in connexin 43, and which are fully viable, have recently been developed. Unfortunately, the bone phenotype of different connexin 43 deficient models has been variable. To address this issue, we used an osteocalcin driven Cre-lox system to create osteoblast and osteocyte specific connexin 43 deficient mice. These mice displayed bone loss as a result of increased bone resorption and osteoclastogenesis. The mechanism underlying this increased osteoclastogenesis included increases in the osteocytic, but not osteoblastic, RANKL/OPG ratio. Previous in vitro 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 enhancing the anabolic response of bone to mechanical loading.
authors: Division of Musculoskeletal Sciences, Department of Orthopaedics and Rehabilitation, Penn State College of Medicine, Hershey, Pennsylvania, United States of America.
authors: Yue
authors: Y
authors: Zhang
authors: Emmanuel M
authors: EM
authors: Paul
authors: Vikram
authors: V
authors: Sathyendra
authors: Andrew
authors: A
authors: Davison
authors: Neil
authors: N
authors: Sharkey
authors: Sarah
authors: S
authors: Bronson
authors: Sundar
authors: S
authors: Srinivasan
authors: Ted S
authors: TS
authors: Gross
authors: Henry J
authors: HJ
authors: Donahue
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D015519:Bone Density / Q000235:genetics; D001862:Bone Resorption / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D001842:Bone and Bones / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D002450:Cell Communication / Q000235:genetics; D002460:Cell Line; D018031:Connexin 43 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D017629:Gap Junctions / Q000378:metabolism*; D017353:Gene Deletion; D006801:Humans; D008297:Male; D055595:Mechanical Phenomena; D051379:Mice; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology*; D010011:Osteocytes / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis / Q000235:genetics; D053244:Osteoprotegerin / Q000235:genetics; D053245:RANK Ligand / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
chemical_list: D018031:Connexin 43; D053244:Osteoprotegerin; D053245:RANK Ligand; D012333:RNA, Messenger; C506031:Tnfrsf11b protein, mouse