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.
1,25-Dihydroxyvitamin D(3) (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 1alpha-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.
Barthel
Thomas K
TK
Department of Biochemistry & Molecular Biophysics, The University of Arizona, Tucson, AZ 85724, USA.
Mathern
Douglas R
DR
Whitfield
G Kerr
GK
Haussler
Carol A
CA
Hopper
H Andrew
HA
Hsieh
Jui-Cheng
JC
Slater
Stephanie A
SA
Hsieh
Grace
G
Kaczmarska
Magdalena
M
Jurutka
Peter W
PW
Kolek
Olga I
OI
Ghishan
Fayez K
FK
Haussler
Mark R
MR
D000818:Animals; D001483:Base Sequence; D001842:Bone and Bones / Q000166:cytology / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002454:Cell Differentiation; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006706:Homeostasis; D006801:Humans; D051379:Mice; D008903:Minerals / Q000378:metabolism*; D010758:Phosphorus / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D018167:Receptors, Calcitriol / Q000378:metabolism*; D014158:Transcription, Genetic / Q000235:genetics; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000378:metabolism
C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; C505605:Fgf23 protein, rat; D008903:Minerals; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; C118756:dihydroxy-vitamin D3; D014807:Vitamin D; D010758:Phosphorus; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D002118:Calcium