Overexpression of Gα11 in Osteoblast Lineage Cells Suppresses the Osteoanabolic Response to Intermittent PTH and Exercise.
Intermittent parathyroid hormone (iPTH) treatment and mechanical loading are osteoanabolic stimuli that are partially mediated through actions on G protein-coupled receptors (GPCRs). GPCR signaling can be altered by heterotrimeric G protein Gα subunits levels, which can therefore lead to altered responses to such stimuli. Previous studies have suggested that enhanced signaling through the Gαq/11 pathway inhibits the osteoanabolic actions of PTH. The influence of Gαq/11 signaling on mechanotransduction, however, has not been reported in vivo. Using transgenic mice that specifically overexpress Gα11 in osteoblast lineage cells (G11-Tg mice), we investigated the skeletal effects of elevated Gα11 levels on iPTH and mechanical loading by treadmill exercise. Both regimens increased trabecular and cortical bone in Wild-Type (WT) mice as a result of increased bone formation. In G11-Tg mice, there was no change in trabecular or cortical bone and no increase in bone formation in response to iPTH or exercise. While exercise reduced osteoclast parameters in WT mice, these changes were diminished in G11-Tg mice as expression of M-csf and Trap remained increased. Collectively, our results suggest that osteoblastic upregulation of Gα11 is inhibitory to osteoanabolic actions of both PTH and exercise, and that its suppression may be a promising target for treating bone loss.
Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada.
Ariana
A
Dela Cruz
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.|Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.
Marc D
MD
Grynpas
Department of Pharmacology and Toxicology, Faculty of Medicine, University of Toronto, 1 King's College Circle, Room 4342, Toronto, ON, M5S 1A8, Canada. jane.mitchell@utoronto.ca.
Jane
J
Mitchell
D000818:Animals; D001696:Biomechanical Phenomena; D001842:Bone and Bones / Q000502:physiology; D019070:Cell Lineage; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000378:metabolism*; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism; D008297:Male; D040542:Mechanotransduction, Cellular; D051379:Mice; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000378:metabolism*; D010010:Osteoclasts / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D010281:Parathyroid Hormone / Q000378:metabolism*; D010805:Physical Conditioning, Animal; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction; D013314:Stress, Mechanical; D055114:X-Ray Microtomography
D010281:Parathyroid Hormone; D043562:Receptors, G-Protein-Coupled; D016173:Macrophage Colony-Stimulating Factor; D043802:GTP-Binding Protein alpha Subunits, Gq-G11
Exercise; Gα11 protein; Intermittent PTH; Osteoblasts; Osteoclasts; Trabecular bone