The nuclear vitamin D receptor controls the expression of genes encoding factors which feed the "Fountain of Youth" to mediate healthful aging.
The nuclear vitamin D receptor (VDR) binds 1,25-dihydroxyvitamin D3 (1,25D), its high affinity renal endocrine ligand, to signal intestinal calcium and phosphate absorption plus bone remodeling, generating a mineralized skeleton free of rickets/osteomalacia with a reduced risk of osteoporotic fractures. 1,25D/VDR signaling regulates the expression of TRPV6, BGP, SPP1, LRP5, RANKL and OPG, while achieving feedback control of mineral ions to prevent age-related ectopic calcification by governing CYP24A1, PTH, FGF23, PHEX, and klotho transcription. Vitamin D also elicits numerous intracrine actions when circulating 25-hydroxyvitamin D3, the metabolite reflecting vitamin D status, is converted to 1,25D locally by extrarenal CYP27B1, and binds VDR to promote immunoregulation, antimicrobial defense, xenobiotic detoxification, anti-inflammatory/anticancer actions and cardiovascular benefits. VDR also affects Wnt signaling through direct interaction with beta-catenin, ligand-dependently blunting beta-catenin mediated transcription in colon cancer cells to attenuate growth, while potentiating beta-catenin signaling via VDR ligand-independent mechanisms in osteoblasts and keratinocytes to function osteogenically and as a pro-hair cycling receptor, respectively. Finally, VDR also drives the mammalian hair cycle in conjunction with the hairless corepressor by repressing SOSTDC1, S100A8/S100A9, and PTHrP. Hair provides a shield against UV-induced skin damage and cancer in terrestrial mammals, illuminating another function of VDR that facilitates healthful aging.
Haussler
Mark R
MR
Department of Basic Medical Sciences, The University of Arizona, College of Medicine-Phoenix in partnership with Arizona State University, Phoenix, AZ 85004-2157, United States. haussler@u.arizona.edu
Haussler
Carol A
CA
Whitfield
G Kerr
GK
Hsieh
Jui-Cheng
JC
Thompson
Paul D
PD
Barthel
Thomas K
TK
Bartik
Leonid
L
Egan
Jan B
JB
Wu
Yifei
Y
Kubicek
Jana L
JL
Lowmiller
Christine L
CL
Moffet
Eric W
EW
Forster
Ryan E
RE
Jurutka
Peter W
PW
D000375:Aging; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism*; D000089703:Fibroblast Growth Factor-23; D005786:Gene Expression Regulation; D006801:Humans; D015603:Keratinocytes / Q000166:cytology; D051379:Mice; D008954:Models, Biological; D053495:Osteopontin / Q000378:metabolism; D010710:Phosphates / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000378:metabolism*; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D010710:Phosphates; D018167:Receptors, Calcitriol; D051153:Wnt Proteins; D051176:beta Catenin; D053495:Osteopontin; D000089703:Fibroblast Growth Factor-23; D002118:Calcium