Quinn SJ, Thomsen AR, Pang JL, Kantham L, Bräuner-Osborne H, Pollak M, Goltzman D, Brown EM. Interactions between calcium and phosphorus in the regulation of the production of fibroblast growth factor 23 in vivo. Am J Physiol Endocrinol Metab 304: E310 -E320, 2013. First published December 11, 2012; doi:10.1152/ajpendo.00460.2012.-Calcium and phosphorus homeostasis are highly interrelated and share common regulatory hormones, including FGF23. However, little is known about calcium's role in the regulation of FGF23. We sought to investigate the regulatory roles of calcium and phosphorus in FGF23 production using genetic mouse models with targeted inactivation of PTH (PTH KO) or both PTH and the calcium-sensing receptor (CaSR; PTHCaSR DKO). In wild-type, PTH KO, and PTH-CaSR DKO mice, elevation of either serum calcium or phosphorus by intraperitoneal injection increased serum FGF23 levels. In PTH KO and PTH-CaSR DKO mice, however, increases in serum phosphorus by dietary manipulation were accompanied by severe hypocalcemia, which appeared to blunt stimulation of FGF23 release. Increases in dietary phosphorus in PTH-CaSR DKO mice markedly decreased serum 1,25-dihydroxyvitamin D 3 [1,25(OH)2D3] despite no change in FGF23, suggesting direct regulation of 1,25(OH)2D3 synthesis by serum phosphorus. Calcium-mediated increases in serum FGF23 required a threshold level of serum phosphorus of about 5 mg/dl. Analogously, phosphorus-elicited increases in FGF23 were markedly blunted if serum calcium was less than 8 mg/dl. The best correlation between calcium and phosphorus and serum FGF23 was found between FGF23 and the calcium ϫ phosphorus product. Since calcium stimulated FGF23 production in the PTH-CaSR DKO mice, this effect cannot be mediated by the full-length CaSR. Thus the regulation of FGF23 by both calcium and phosphorus appears to be fundamentally important in coordinating the serum levels of both mineral ions and ensuring that the calcium ϫ phosphorus product remains within a physiological range. fibroblast growth factor 23; calcium ϫ phosphorus product; 1,25-dihydroxyvitamin D3; parathyroid hormone; calcium-sensing receptor CALCIUM AND PHOSPHORUS HOMEOSTASIS are highly dependent on one another, and changes in the serum level of either calcium or phosphorus will in many cases lead to secondary changes in the serum level of the other. Fibroblast growth factor 23 (FGF23) is a newly discovered hormone that is implicated in phosphorus homeostasis, and dysregulation of FGF23 may result in several disorders of phosphorus homeostasis (1,24,38). FGF23 is expressed in and released from osteoblasts and osteocytes in response to hyperphosphatemia and 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] (19, 20, 39). In the renal tubule, FGF23 binds to FGF receptors and their cofactor Klotho, causing inhibition of the expression of the sodiumdependent phosphate cotransporters Npt2a and Npt2c, thereby resulting in less renal phosphorus reabsorption (11,21,35,40,41). In addition, FGF23 inhibits expression of the 1␣-hydroxylase enzyme, l...
