FGF-23–Klotho signaling stimulates proliferation and prevents vitamin D–induced apoptosis

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Abstract
Fibroblast growth factor 23 (FGF-23) and Klotho are secretory proteins that regulate mineral-ion metabolism. Fgf-23−/− or Klotho−/− knockout mice exhibit several pathophysiological processes consistent with premature aging including severe atrophy of tissues. We show that the signal transduction pathways initiated by FGF-23–Klotho prevent tissue atrophy by stimulating proliferation and preventing apoptosis caused by excessive systemic vitamin D. Because serum levels of active vitamin D are greatly increased upon genetic ablation of Fgf-23 or Klotho, we find that these molecules have a dual role in suppression of apoptotic actions of vitamin D through both negative regulation of 1α-hydroxylase expression and phosphoinositide-3 kinase–dependent inhibition of caspase activity. These data provide new insights into the physiological roles of FGF-23 and Klotho.