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Published online
doi:10.1083/jcb.200803024
The Journal of Cell Biology, Vol. 182, No. 3, 459-465
The Rockefeller University Press, 0021-9525 $30.00
© Medici et al.
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FGF-23–Klotho signaling stimulates proliferation and prevents vitamin D–induced apoptosis



Damian Medici1,2, Mohammed S. Razzaque1, Stephelynn DeLuca1, Trent L. Rector3, Bo Hou1,2, Kihwa Kang4, Regina Goetz5, Moosa Mohammadi5, Makoto Kuro-o6, Bjorn R. Olsen1,2, and Beate Lanske1

1 Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115
2 Departments of Cell Biology and 3 Genetics, Harvard Medical School, Boston, MA 02115
4 Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115
5 Department of Pharmacology, New York University School of Medicine, New York, NY 10016
6 Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390

Correspondence to Beate Lanske: beate_lanske{at}hsdm.harvard.edu

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 1{alpha}-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.

Abbreviations used in this paper: ERK, extracellular signal–regulated kinase; I{kappa}B, inhibitor {kappa}B; PI3K, phosphoinositide-3 kinase; PTEC, proximal tubule epithelial cells.

© 2008 Medici et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).


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