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; PTH-CaSR 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)(2)D(3)] despite no change in FGF23, suggesting direct regulation of
1,25(OH)(2)D(3) 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 ×
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 ×
phosphorus product remains within a physiological range.