title: Increased bone density in mice lacking the proton receptor OGR1.
abstract: Chronic metabolic acidosis stimulates cell-mediated calcium efflux from bone through osteoblastic prostaglandin E2-induced stimulation of receptor activator of NF-kB ligand leading to increased osteoclastic bone resorption. Osteoblasts express the proton-sensing G-protein-coupled receptor OGR1, which activates inositol phosphate-mediated intracellular calcium. Proton-induced osteoblastic intracellular calcium signaling requires ovarian cancer G-protein-coupled receptor 1 (OGR1), suggesting that OGR1 is the sensor activated during acidosis to cause bone resorption. Growing mice produce large amounts of metabolic acids, which must be buffered, primarily by bone, before excretion by the kidney. Here we tested whether lack of OGR1 inhibits proton-induced bone resorption by measuring bone mineral density by micro-computed tomography and histomorphometry in 8-week-old male OGR1(-/-) and C57/Bl6 wild type mice. OGR1(-/-) mice have normal skeletal development with no atypical gross phenotype. Trabecular and cortical bone volume was increased in tibiae and vertebrae from OGR1(-/-). There were increased osteoblast numbers on the cortical and trabecular surfaces of tibiae from OGR1(-/-) mice, increased endocortical and trabecular bone formation rates, and osteoblastic gene expression. Osteoclast numbers and surface were increased in tibiae of OGR1(-/-) mice. Thus, in rapidly growing mice, lack of OGR1 leads to increased bone mass with increased bone turnover and a greater increase in bone formation than resorption. This supports the important role of the proton receptor OGR1 in the response of bone to protons.
authors.affiliation: Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA. Electronic address: nancy_krieger@urmc.rochester.edu.
authors.forename: Nancy S
authors.initials: NS
authors.lastname: Krieger
authors.affiliation: Department of Pathology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
authors.forename: Zhenqiang
authors.initials: Z
authors.lastname: Yao
authors.affiliation: Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
authors.forename: Kelly
authors.initials: K
authors.lastname: Kyker-Snowman
authors.affiliation: Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
authors.forename: Min Ho
authors.initials: MH
authors.lastname: Kim
authors.affiliation: Department of Pathology, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
authors.forename: Brendan F
authors.initials: BF
authors.lastname: Boyce
authors.affiliation: Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Bushinsky
mesh_terms: D000818:Animals; D015519:Bone Density / Q000235:genetics; D049109:Cell Proliferation; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D005838:Genotype; D006863:Hydrogen-Ion Concentration; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010006:Osteoblasts / Q000378:metabolism*; D010012:Osteogenesis / Q000235:genetics; D010641:Phenotype; D043562:Receptors, G-Protein-Coupled / Q000172:deficiency* / Q000235:genetics; D013977:Tibia / Q000000981:diagnostic imaging / Q000378:metabolism*; D013997:Time Factors; D055114:X-Ray Microtomography
chemical_list: C525539:GPR68 protein, mouse; D043562:Receptors, G-Protein-Coupled
keywords: OGR1; bone formation; bone resorption; metabolic acidosis; proton