Effect of Osteoblast‐Specific Deletion of the Proton Receptor OGR1

Abstract

Metabolic acidosis (MET) stimulates bone resorption through inhibition of osteoblast (OB) bone formation and stimulation of osteoclast (OC) bone resorption. We found that OGR1, a G protein‐coupled proton (H + )‐sensing receptor, was critical for initial H + signaling in the OB. In mice with a global deletion of OGR1, we demonstrated that loss of OGR1 impairs H + ‐induced bone resorption, leading to increased bone density through effects on both the OB and OC. Using an OC‐specific deletion of OGR1, we found that MET directly activates OGR1 in the OC. To determine if the response of OGR1 to MET in the OB is independent of a response in OCs and to characterize direct activation of OGR1 in the OB, we studied female mice with an OB‐specific deletion of OGR1 (OB‐cKO) and differentiated osteoblasts derived from marrow of OB‐cKO and wild‐type (WT) mice. In OB‐cKO mice, we found increased bone area in both tibial and femoral cortical bone. Specific loss of OB OGR1 increased in vitro mineralization, alkaline phosphatase activity, and expression of osteoblast‐specific genes compared with WT with no alteration in OC activity. MET stimulation of OB cox2 and fgf23 gene expression was inhibited in OB‐cKO OB. These results indicate that MET activation of OGR1 in the OB is independent of the response in the OC and that OGR1 in both cell types is required for a complete response to MET. Characterization of the role of OGR1 in MET‐induced bone resorption will improve our understanding of bone loss associated with metabolic acidosis in patients with chronic kidney disease. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Recent advances in acid sensing by G protein coupled receptors

“…An individual with a heterozygous OGR1 exonic deletion was identified, who was described as healthy but having suffered a “vertebral fracture during light physical activity” [ 69 ]. This study is a first correlation between OGR1 loss-of-function and osteoporosis in humans, and it ties in very nicely with the studies investigating impact of osteoclast- and osteoblast-specific OGR1 knockout discussed above [ 36 , 37 ]. However, neither OGR1 ko mice nor human individuals with functional deletion of OGR1 have been reported to have defects in bone mineralisation.…”

“…These findings were then extended in a second study that sought to address potential differences in roles for OGR1 in osteoclasts and osteoblasts. Using osteoblast- and osteoclast-specific OGR1 knockout, this study demonstrated that OGR1 stimulation in osteoblasts and osteoclasts resulted in cell-type specific responses under conditions of metabolic acidosis (osteoblasts: cox2 , fgf23 gene expression; osteoclasts: mineralisation and alkaline phosphatase activity as well as osteoclast-specific gene expression) that both contribute different aspects to OGR1-mediated bone loss under conditions of metabolic acidosis [ 37 ].…”

Role of pH-sensing receptors in colitis

“…The extracellular acidification-induced expression of these OGR1-dependent genes was greatly enhanced under hypoxic conditions in human intestinal macrophages, and this effect was reversed by NF-κB inhibition [ 23 ]. OGR1 has also been implicated in other physiological processes, including kidney function and bone metabolism [ 50 , 66 ]. Of particular interest is the recent observation that a homozygous loss of function of OGR1 was described in families with amelogenesis imperfecta, suggesting that OGR1 is required for dental enamel formation [ 101 ].…”

Ossäre Bedeutung von Mineral- und Heilwässern: Physiologie und epidemiologische Evidenz

“…Auf diese Weise ist das Knochenremodelling eng an die extrazelluläre Konzentration der Oxoniumionen [H 3 O + ) gekoppelt. Deutlich wird dies bei chronischer Azidämie, wo die Hochregulation des ORG1-Signalwegs mit einer gesteigerten Knochenresorption einhergeht [115,116], verbunden mit einer erhöhten Ausscheidung von Calcium über den Urin [117]. Eine gestörte Mikroarchitektur des Knochens und ein erhöhtes Frakturrisiko sind die Folgen [118,119].…”