Fibroblast growth factor-23 abolishes 1,25-dihydroxyvitamin D<inf>3</inf>-enhanced duodenal calcium transport in male mice

Abstract

Despite being widely recognized as the important bone-derived phosphaturic hormone, whether fibroblast growth factor (FGF)-23 modulated intestinal calcium absorption remained elusive. Since FGF-23 could reduce the circulating level of 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D3], FGF-23 probably compromised the 1,25(OH) 2 D3 induced intestinal calcium absorption. FGF-23 may also exert an inhibitory action directly through FGF receptors (FGFR) in the intestinal cells. Herein, we demonstrated by Ussing chamber technique that male mice administered 1 μg/kg 1,25(OH) 2 D 3 sc daily for 3 days exhibited increased duodenal calcium absorption, which was abolished by concurrent intravenous injection of recombinant mouse FGF-23. This FGF-23 administration had no effect on the background epithelial electrical properties, i.e., short-circuit current, transepithelial potential difference, and resistance. Immunohistochemical evidence of protein expressions of FGFR isoforms 14 in mouse duodenal epithelial cells suggested a possible direct effect of FGF-23 on the intestine. This was supported by the findings that FGF-23 directly added to the serosal compartment of the Ussing chamber and completely abolished the 1,25(OH) 2 D3-induced calcium absorption in the duodenal tissues taken from the 1,25(OH) 2 D 3 -treated mice. However, direct FGF-23 exposure did not decrease the duodenal calcium absorption without 1,25(OH) 2 D 3 preinjection. The observed FGF-23 action was mediated by MAPK/ERK, p38 MAPK, and PKC. Quantitative real-time PCR further showed that FGF-23 diminished the 1,25(OH) 2 D3-induced upregulation of TRPV5, TRPV6, and calbindin-D 9k , but not PMCA 1b expression in the duodenal epithelial cells. In conclusion, besides being a phosphatonin, FGF-23 was shown to be a novel calcium-regulating hormone that acted directly on the mouse intestine, thereby compromising the 1,25(OH) 2 D 3 -induced calcium absorption. © 2012 the American Physiological Society.