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 RANKL leading to increased osteoclastic bone resorption. Osteoblasts express the proton-sensing G-protein coupled receptor, OGR1, which activates IP3-mediated intracellular calcium. Proton-induced osteoblastic intracellular calcium signaling requires OGR1, suggesting 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, prior to excretion by the kidney. Here we tested whether lack of OGR1 inhibits proton-induced bone resorption by measuring bone mineral density by μCT 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.

Coincidence Detection of Membrane Stretch and Extracellular pH by the Proton-Sensing Receptor OGR1 (GPR68)

“…OGR1 does not desensitize and is the only proton-sensing GPCR coupling to changes in [Ca 2+ ] i [14,27], which determine a plethora of physiological as well as underlie pathological processes. OGR1 affects a number of distinct cellular processes and, in light of our findings, its role in enamel formation [28] and bone development [29][30][31] is particularly intriguing: enamel and bone are the hardest materials in the human body, and enamel formation and bone development both require cycles of extracellular acidification [32,33].…”

Increased Osteoclast and Decreased Osteoblast Activity Causes Reduced Bone Mineral Density and Quality in Genetic Hypercalciuric Stone‐Forming Rats

“…Calvarial cells were isolated from 2‐ to 3‐day‐old GHS and SD rat pups by sequential collagenase digestion as previously described . The isolated cells were plated in six‐well plates at a density of 5 × 10 5 cells/well in Dulbecco's modified essential medium.…”

“…Calvarial cells were isolated from 2-to 3-day-old GHS and SD rat pups by sequential collagenase digestion as previously described. (46,47) The isolated cells were plated in six-well plates at a density of 5 × 10 5 cells/well in Dulbecco's modified essential medium. At confluence, fresh α-MEM, containing 10% heatinactivated FBS and 1% L-glutamine, supplemented with ascorbic acid (50 μg/mL) and 10mM β-glycerophosphate, was added to the cells to induce cell differentiation and mineralization.…”

Role of proton receptor OGR1 in bone response to metabolic acidosis?

“…How can one explain these somewhat counterintuitive findings? Krieger et al 8 have not been able to provide a definitive answer to this question. It is possible that the deletion of OGR1 induces a potent osteoblast stimulation and that a predominant effect on the osteoblast led to an anabolic phenotype.…”

“…The hydrogen is secreted into the bone using the same ion pump (V-ATPase) as found in renal tubular cells; the bicarbonate is secreted into the marrow spaces. 6 In this issue of the journal, Krieger et al 8 (2016) report the results of an intriguing study whose hypothesis was that lack of OGR1 inhibits acidosis-induced bone resorption. The hypothesis was based on the investigators' previous in vitro studies, which showed that H þ activation of this receptor resulted in increased intracellular Ca 2þ signaling in osteoblasts, and that the inhibition of OGR1 activity by CuCl 2 prevented H þ -stimulated bone resorption in cultured neonatal mouse calvariae.…”