Nancy S. Krieger 1/1/16-12/31/16 Mechanism of FGF23 Regulation by Metabolic Acidosis 4/16/16-3/31/2020 Hypercalciuria and Bone Quality in the Genetic Hypercalciuric Stone-Forming Rats This research examines the signal transduction steps involved in the response of bone to metabolic acidosis. In vitro studies in bone have shown that prostaglandins mediate acid-induced calcium release from bone. This occurs by direct stimulation of the enzyme, cyclooxygenase 2, which catalyzes the rate-limiting step in prostaglandin synthesis in the osteoblast and subsequent stimulation of receptor activator of NFκB ligand, ultimately resulting in enhanced osteoclastic bone resorption. We are currently studying the initial intracellular signals that mediate these effects, beginning with defining the G-protein coupled proton sensing receptor activated in the osteoblast. Understanding the signaling pathways involved in acid stimulation of prostaglandin synthesis in the osteoblast could provide insights into therapeutic approaches to treat or prevent the renal osteodystrophy associated with metabolic acidosis.