title: Osteoblast connexin43 modulates skeletal architecture by regulating both arms of bone remodeling.
abstract: Connexin43 (Cx43) has an important role in skeletal homeostasis, and Cx43 gene (Gja1) mutations have been linked to oculodentodigital dysplasia (ODDD), a human disorder characterized by prominent skeletal abnormalities. To determine the function of Cx43 at early steps of osteogenesis and its role in the ODDD skeletal phenotype, we have used the Dermo1 promoter to drive Gja1 ablation or induce an ODDD mutation in the chondro-osteogenic linage. Both Gja1 null and ODDD mutant mice develop age-related osteopenia, primarily due to a progressive enlargement of the medullary cavity and cortical thinning. This phenotype is the consequence of a high bone turnover state, with increased endocortical osteoclast-mediated bone resorption and increased periosteal bone apposition. Increased bone resorption is a noncell autonomous defect, caused by exuberant stimulation of osteoclastogenesis by Cx43-deficient bone marrow stromal cells, via decreased Opg production. The latter is part of a broad defect in osteoblast differentiation and function, which also results in abnormal structural and material properties of bone leading to decreased resistance to mechanical load. Thus Cx43 in osteogenic cells is a critical regulator of both arms of the bone remodeling cycle, its absence causing structural changes remindful of aged or disused bone.
authors.affiliation: Department of Internal Medicine and Cell Biology, Washington University School of Medicine, St. Louis, MO 63110, USA. mwatkins@dom.wustl.edu
authors.forename: Marcus
authors.initials: M
authors.lastname: Watkins
authors.forename: Susan K
authors.initials: SK
authors.lastname: Grimston
authors.forename: Jin Yi
authors.initials: JY
authors.lastname: Norris
authors.forename: Bertrand
authors.initials: B
authors.lastname: Guillotin
authors.forename: Angela
authors.initials: A
authors.lastname: Shaw
authors.forename: Elia
authors.initials: E
authors.lastname: Beniash
authors.forename: Roberto
authors.initials: R
authors.lastname: Civitelli
mesh_terms: D000367:Age Factors; D000818:Animals; D001848:Bone Diseases, Developmental / Q000235:genetics / Q000378:metabolism; D016723:Bone Remodeling / Q000235:genetics*; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism; D001842:Bone and Bones; D002450:Cell Communication; D002454:Cell Differentiation; D002478:Cells, Cultured; D018031:Connexin 43 / Q000172:deficiency / Q000235:genetics; D015870:Gene Expression; D056726:Genetic Association Studies; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism*; D010012:Osteogenesis / Q000502:physiology; D053244:Osteoprotegerin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D011401:Promoter Regions, Genetic; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism
chemical_list: D018031:Connexin 43; D053244:Osteoprotegerin; C506031:Tnfrsf11b protein, mouse