Kevin K. Frick

Mechanism of Acidosis Regulation of Prostaglandin-Mediated Bone Resorption

Renal Research Institute – funded since 2001, refunded in 2010

This research examines the mechanisms by which metabolic acidosis enhances bone resorption. Metabolic acidosis induces osteoblast cyclooxygenase 2 RNA levels, enhancing release of prostaglandin E2 and subsequent stimulation of receptor activator of NFκB ligand (RANKL) expression, leading to enhanced osteoclastic bone resorption. Mouse calvarial osteoblasts express several proton-sensing G-protein coupled receptors, including OGR1, the ovarian cancer G-protein coupled receptor 1. We have demonstrated that perfusion of osteoblasts with medium simulating metabolic acidosis (i.e., decreased [HCO3-], MET) induces a rapid, asynchronus transient increase in intracellular Ca (Cai) in multiple cells. A similar increase in Cai occurs in CHO cells transfected with mouse OGR1 and perfused with MET, suggesting that OGR1 transduces responses to the decrease in extracellular pH. In contrast to the marked effects of MET on bone calcium efflux, isohydric respiratory acidosis (i.e., increased Pco2, RESP) has very little effect on resorption. Perfusion of primary bone cells with MET induces a significantly greater increase in Cai than does perfusion with RESP. In contrast, little difference in Cai was seen when OGR1-transfected CHO cells were perfused with MET as compared to RESP. These data suggest that osteoblast sensing of HCO3- or CO2 modulates proton-sensing. We are using primary bone cells from OGR1 null mice or wild type mice to determine the difference in induction of Cai transients in these cells by MET versus RESP. We are also determining the effects of inhibiting bicarbonate transport on the induction of Cai transients by MET and RESP in wild type and OGR1 null osteoblastic cells.