TY - JOUR
T1 - 1,25-Dihydroxyvitamin D3/VDR-mediated induction of FGF23 as well as transcriptional control of other bone anabolic and catabolic genes that orchestrate the regulation of phosphate and calcium mineral metabolism
AU - Barthel, Thomas K.
AU - Mathern, Douglas R.
AU - Whitfield, G. Kerr
AU - Haussler, Carol A.
AU - Hopper IV, H. Andrew
AU - Hsieh, Jui Cheng
AU - Slater, Stephanie A.
AU - Hsieh, Grace
AU - Kaczmarska, Magdalena
AU - Jurutka, Peter W.
AU - Kolek, Olga I.
AU - Ghishan, Fayez K.
AU - Haussler, Mark R.
N1 - Funding Information:
This work was supported by National Institutes of Health grants to MRH (DK33351 and DK063930), TKB (AG20036) and FKG (DK33209).
PY - 2007/3
Y1 - 2007/3
N2 - 1,25-Dihydroxyvitamin D3 (1,25D) is known primarily as a regulator of calcium, but 1,25D also promotes phosphate absorption from intestine, reabsorption from kidney, and bone mineral resorption. FGF23 is a newly discovered phosphaturic hormone that, like PTH, lowers serum phosphate by inhibiting renal reabsorption via Npt2a. We show that 1,25D strongly upregulates FGF23 in bone. FGF23 then represses 1α-OHase activity in kidney, thus preventing spiraling induction of FGF23 by 1,25D. We also report that LRP5, Runx2, TRPV6, and Npt2c, all anabolic toward bone, and RANKL, which is catabolic, are transcriptionally regulated by 1,25D. This coordinated regulation together with that of FGF23 and PTH allows 1,25D to play a central role in maintaining calcium and phosphate homeostasis and bone metabolism. In the cases of LRP5, Runx2, TRPV6, and Npt2c we show that transcriptional regulation results at least in part from direct binding of VDR near the relevant gene promoter. Finally, because 1,25D induces FGF23, and FGF23 in turn represses 1,25D synthesis, a reciprocal relationship is established with FGF23 indirectly curtailing 1,25D-mediated intestinal absorption and counterbalancing renal reabsorption of phosphate. This newly revealed FGF23/1,25D/Pi axis is comparable in significance to phosphate and bone metabolism as the PTH/1,25D/Ca axis is to calcium homeostasis.
AB - 1,25-Dihydroxyvitamin D3 (1,25D) is known primarily as a regulator of calcium, but 1,25D also promotes phosphate absorption from intestine, reabsorption from kidney, and bone mineral resorption. FGF23 is a newly discovered phosphaturic hormone that, like PTH, lowers serum phosphate by inhibiting renal reabsorption via Npt2a. We show that 1,25D strongly upregulates FGF23 in bone. FGF23 then represses 1α-OHase activity in kidney, thus preventing spiraling induction of FGF23 by 1,25D. We also report that LRP5, Runx2, TRPV6, and Npt2c, all anabolic toward bone, and RANKL, which is catabolic, are transcriptionally regulated by 1,25D. This coordinated regulation together with that of FGF23 and PTH allows 1,25D to play a central role in maintaining calcium and phosphate homeostasis and bone metabolism. In the cases of LRP5, Runx2, TRPV6, and Npt2c we show that transcriptional regulation results at least in part from direct binding of VDR near the relevant gene promoter. Finally, because 1,25D induces FGF23, and FGF23 in turn represses 1,25D synthesis, a reciprocal relationship is established with FGF23 indirectly curtailing 1,25D-mediated intestinal absorption and counterbalancing renal reabsorption of phosphate. This newly revealed FGF23/1,25D/Pi axis is comparable in significance to phosphate and bone metabolism as the PTH/1,25D/Ca axis is to calcium homeostasis.
KW - Bone mineral metabolism
KW - Calcium metabolism
KW - Fibroblast growth factor-23
KW - LRP5
KW - Npt2c
KW - PHEX
KW - Phosphate metabolism
KW - RANKL
KW - Runx2
KW - TRPV6
KW - Vitamin D receptor
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UR - http://www.scopus.com/inward/citedby.url?scp=33947192418&partnerID=8YFLogxK
U2 - 10.1016/j.jsbmb.2006.12.054
DO - 10.1016/j.jsbmb.2006.12.054
M3 - Article
C2 - 17293108
AN - SCOPUS:33947192418
SN - 0960-0760
VL - 103
SP - 381
EP - 388
JO - Journal of Steroid Biochemistry and Molecular Biology
JF - Journal of Steroid Biochemistry and Molecular Biology
IS - 3-5
ER -