The Increase in FGF23 Induced by Calcium Is Partially Dependent on Vitamin D Signaling

Background: Increased FGF23 levels are an early pathological feature in chronic kidney disease (CKD), causing increased cardiovascular risk. The regulation of FGF23 expression is complex and not completely understood. Thus, Ca(2+) has been shown to induce an increase in FGF23 expression, but whether that increase is mediated by simultaneous changes in parathyroid hormone (PTH) and/or vitamin D is not fully known. Methods: Osteoblast-like cells (OLCs) from vitamin D receptor (VDR)(+/+) and VDR(−/−) mice were incubated with Ca(2+) for 18 h. Experimental hypercalcemia was induced by calcium gluconate injection in thyro-parathyroidectomized (T-PTX) VDR (+/+) and VDR(−/−) mice with constant PTH infusion. Results: Inorganic Ca(2+) induced an increase in FGF23 gene and protein expression in osteoblast-like cells (OLCs), but the increase was blunted in cells lacking VDR. In T-PTX VDR (+/+) and VDR(−/−) mice with constant PTH levels, hypercalcemia induced an increase in FGF23 levels, but to a lower extent in animals lacking VDR. Similar results were observed in FGF23 expression in bone. Renal and bone 1α-hydroxylase expression was also modulated. Conclusions: Our study demonstrates that Ca(2+) can increase FGF23 levels independently of vitamin D and PTH, but part of the physiological increase in FGF23 induced by Ca(2+) is mediated by vitamin D signaling.