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The role of vitamin D in the FGF23, klotho, and phosphate bone-kidney endocrine axis

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Abstract

1,25-dihydroxyvitamin D (1,25D), through association with the nuclear vitamin D receptor (VDR), exerts control over a novel endocrine axis consisting of the bone-derived hormone FGF23, and the kidney-expressed klotho, CYP27B1, and CYP24A1 genes, which together prevent hyperphosphatemia/ectopic calcification and govern the levels of 1,25D to maintain bone mineral integrity while promoting optimal function of other vital tissues. When occupied by 1,25D, VDR interacts with RXR to form a heterodimer that binds to VDREs in the region of genes directly controlled by 1,25D (e.g., FGF23, klotho, Npt2c, CYP27B1 and CYP24A1). By recruiting complexes of comodulators, activated VDR initiates a series of events that induces or represses the transcription of genes encoding proteins such as: the osteocyte-derived hormone, FGF23; the renal anti-senescence factor and protein co-receptor for FGF23, klotho; other mediators of phosphate transport including Npt2a/c; and vitamin D hormone metabolic enzymes, CYP27B1 and CYP24A1. The mechanism whereby osteocytes are triggered to release FGF23 is yet to be fully defined, but 1,25D, phosphate, and leptin appear to play major roles. The kidney responds to FGF23 to elicit CYP24A1-catalyzed detoxification of the 1,25D hormone while also repressing both Npt2a/c to mediate phosphate elimination and CYP27B1 to limit de novo 1,25D synthesis. Comprehension of these skeletal and renal actions of 1,25D should facilitate the development of novel mimetics to prevent ectopic calcification, chronic renal and vascular disease, and promote healthful aging.

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Acknowledgments

We thank Dr. Shigeaki Kato (University of Tokyo), Dr. Ken-ichi Miyamoto and Dr. Hiroko Segawa (University of Tokushima Graduate School) for sharing the data on klotho expression in VDR knockout mice, and Andrew Hopper IV for performing the experiment shown in Fig. 4. Supported by National Institutes of Health grants to M. R. H.

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  1. Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, 85004, USA

    Mark R. Haussler, G. Kerr Whitfield, Ichiro Kaneko, Jui-Cheng Hsieh, Carol A. Haussler & Peter W. Jurutka

  2. Division of Mathematical and Natural Sciences, Arizona State University, Phoenix, AZ, 85306, USA

    Ichiro Kaneko, Ryan Forster, Rimpi Saini & Peter W. Jurutka

  3. Department of Basic Medical Sciences, University of Arizona College of Medicine-Phoenix, 425 N. 5th Street, Phoenix, AZ, 85004-2157, USA

    Mark R. Haussler

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Haussler, M.R., Whitfield, G.K., Kaneko, I. et al. The role of vitamin D in the FGF23, klotho, and phosphate bone-kidney endocrine axis. Rev Endocr Metab Disord 13, 57–69 (2012). https://doi.org/10.1007/s11154-011-9199-8

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