title: Up-regulation of BMP2/4 signaling increases both osteoblast-specific marker expression and bone marrow adipogenesis in Gja1Jrt/+ stromal cell cultures.
abstract: Gja1(Jrt)/+ mice carry a mutation in one allele of the gap junction protein α1 gene (Gja1), resulting in a G60S connexin 43 (Cx43) mutant protein that is dominant negative for Cx43 protein production of <50% of wild-type (WT) levels and significantly reduced gap junction formation and function in osteoblasts and other Cx43-expressing cells. Previously we reported that Gja1(Jrt)/+ mice exhibited early-onset osteopenia caused by activation of osteoclasts secondary to activation of osteoblast lineage cells, which expressed increased RANKL and produced an abnormal resorption-stimulating bone matrix high in BSP content. Gja1(Jrt)/+ mice also displayed early and progressive bone marrow atrophy, with a significant increase in bone marrow adiposity versus WT littermates but no increase in adipose tissues elsewhere in the body. BMP2/4 production and signaling were increased in Gja1(Jrt)/+ trabecular bone and osteogenic stromal cell cultures, which contributed to the up-regulated expression of osteoblast-specific markers (e.g., Bsp and Ocn) in Gja1(Jrt)/+ osteoblasts and increased Pparg2 expression in bone marrow-derived adipoprogenitors in vitro. The elevated levels of BMP2/4 signaling in G60S Cx43-containing cells resulted at least in part from elevated levels of cAMP. We conclude that up-regulation of BMP2/4 signaling in trabecular bone and/or stromal cells increases osteoblast-specific marker expression in hyperactive Gja1(Jrt)/+ osteoblasts and may also increase bone marrow adipogenesis by up-regulation of Pparg2 in the Cx43-deficient Gja1(Jrt)/+ mouse model.
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Tanya
authors.initials: T
authors.lastname: Zappitelli
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
authors.forename: Frieda
authors.initials: F
authors.lastname: Chen
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, ON M5S 1A8, Canada Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada Centre For Modeling Human Disease, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada jane.aubin@utoronto.ca.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Aubin
mesh_terms: D050156:Adipogenesis; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001851:Bone Diseases, Metabolic / Q000235:genetics; D001853:Bone Marrow / Q000378:metabolism* / Q000502:physiology; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism*; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism*; D001842:Bone and Bones / Q000378:metabolism*; D018031:Connexin 43 / Q000235:genetics*; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D010006:Osteoblasts / Q000378:metabolism*; D015398:Signal Transduction; D017154:Stromal Cells / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; C525719:Bmp2 protein, mouse; C525810:Bmp4 protein, mouse; D055396:Bone Morphogenetic Protein 2; D055415:Bone Morphogenetic Protein 4; D018031:Connexin 43; C543076:GJA1 protein, mouse