title: Reduced trabecular bone mass and strength in mice overexpressing Gα11 protein in cells of the osteoblast lineage.
abstract: G protein-coupled receptors (GPCRs) require G proteins for intracellular signaling to regulate a variety of growth and maintenance processes, including osteogenesis and bone turnover. Bone maintenance events may be altered by changes in the activity or level of G proteins, which then modify signaling in bone cells such as osteoblasts. We have previously reported increased levels of Gα11 protein and signaling to phospholipase C/protein kinase C pathways in response to dexamethasone in osteoblastic UMR 106-01 cells. Here we generated pOBCol3.6-GNA11 transgenic mice that overexpress Gα11 protein in cells of the osteoblast lineage (G11-Tg mice). G11-Tg mice exhibit an osteopenic phenotype characterized by significant reductions in trabecular bone mineral density, thickness, number and strength. The numbers of osteoblasts and osteocytes were unchanged in G11-Tg bone, but early markers of osteoblast differentiation, Alp and Bsp, were increased while the late stage differentiation marker Ocn was not changed suggesting reduced osteoblast maturation in G11-Tg trabecular bone which was accompanied by a decreased bone formation rate. Furthermore, in vitro cultures of G11-Tg primary osteoblasts show delayed osteoblast differentiation and mineralization. Histological analyses also revealed increased osteoclast parameters, accompanied by elevated mRNA expression of Trap and Ctsk. mRNA levels of Rankl and M-csf were elevated in vitro in bone marrow stromal cells undergoing osteogenesis and in trabecular bone in vivo. Together, these findings demonstrate that increasing Gα11 protein expression in osteoblasts can alter gene expression and result in a dual mechanism of trabecular bone loss.
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Ariana
authors.initials: A
authors.lastname: Dela Cruz
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Mattocks
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Kim S
authors.initials: KS
authors.lastname: Sugamori
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada.
authors.forename: Marc D
authors.initials: MD
authors.lastname: Grynpas
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario M5S 1A8, Canada. Electronic address: jane.mitchell@utoronto.ca.
authors.forename: Jane
authors.initials: J
authors.lastname: Mitchell
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D015519:Bone Density; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000473:pathology* / Q000503:physiopathology; D002113:Calcification, Physiologic; D002454:Cell Differentiation / Q000235:genetics; D019070:Cell Lineage; D002478:Cells, Cultured; D005269:Femur / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008159:Lumbar Vertebrae / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009929:Organ Size; D009928:Organ Specificity; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D010012:Osteogenesis; D017154:Stromal Cells / Q000378:metabolism; D019076:Transgenes; D055114:X-Ray Microtomography
chemical_list: D043802:GTP-Binding Protein alpha Subunits, Gq-G11
keywords: Bone remodeling; Gα(11) protein; Osteoblast; Osteoclast; Trabecular bone