title: Elevated Gα11 expression in osteoblast lineage cells promotes osteoclastogenesis and leads to enhanced trabecular bone accrual in response to pamidronate.
abstract: Osteoblastic cells indirectly induce osteoclastogenesis in the bone microenvironment by expressing paracrine factors such as RANKL and M-CSF, leading to increased bone resorption. These cytokines can be regulated by a variety of intracellular pathways, which include G protein-coupled receptor signaling. To explore how enhanced signaling of the Gαq/11 pathway in osteoblast lineage cells may mediate osteoclast formation, we cocultured wild-type (WT) preosteoclasts with BMSCs derived from either WT or transgenic mice with osteoblast-specific overexpression of Gα11 (G11-Tg). G11-Tg cocultures had elevated osteoclast numbers with greater resorptive capacity and increased expression of Rankl, Rankl:Opg (osteoprotegerin), and M-csf compared with cocultures with WT BMSCs. As well, cocultures with G11-Tg BMSCs required a higher concentration of OPG to inhibit osteoclast formation and less angiotensin II to increase osteoclast size. These indicate that G11-Tg osteoblasts drive the increased osteoclast formation and osteopenia seen in G11-Tg mice. Pamidronate treatment of G11-Tg mice restored the trabecular bone loss phenotype, as bone mineral density, bone volume, trabecular number, separation, and expressions of osteoblastic and osteoclastic genes were comparable with WT parameters. These changes were characterized by enhanced accumulation of calcified cartilage in trabecular bone, demonstrating that resorption of the cartilaginous intermediate by osteoclasts is more affected by bisphosphonate treatment in G11-Tg mice. In conclusion, overexpression of Gα11 in osteoblastic cells promotes osteoclastogenesis by upregulation of Rankl and M-csf and bone loss by increased osteoclast resorption of the trabecular bone and cartilaginous matrix.
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario Canada;
authors.forename: Ariana
authors.initials: A
authors.lastname: Dela Cruz
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; and Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada.
authors.forename: Marc D
authors.initials: MD
authors.lastname: Grynpas
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario Canada; jane.mitchell@utoronto.ca.
authors.forename: Jane
authors.initials: J
authors.lastname: Mitchell
mesh_terms: D015502:Absorptiometry, Photon; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D015519:Bone Density; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D001854:Bone Marrow Cells; D001862:Bone Resorption / Q000235:genetics / Q000378:metabolism; D000071556:Cancellous Bone / Q000187:drug effects / Q000378:metabolism*; D018920:Coculture Techniques; D004164:Diphosphonates / Q000494:pharmacology; D005269:Femur / Q000000981:diagnostic imaging; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics*; D016173:Macrophage Colony-Stimulating Factor / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics*; D053244:Osteoprotegerin / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D000077268:Pamidronate; D053245:RANK Ligand / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D053244:Osteoprotegerin; D053245:RANK Ligand; D012333:RNA, Messenger; C506031:Tnfrsf11b protein, mouse; C505689:Tnfsf11 protein, mouse; D000804:Angiotensin II; D016173:Macrophage Colony-Stimulating Factor; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D000077268:Pamidronate
keywords: Gα11 protein; bisphosphonates; osteoclastogenesis; trabecular bone