title: FGF23 gene regulation by 1,25-dihydroxyvitamin D: opposing effects in adipocytes and osteocytes.
abstract: In a closed endocrine loop, 1,25-dihydroxyvitamin D3 (1,25D) induces the expression of fibroblast growth factor 23 (FGF23) in bone, with the phosphaturic peptide in turn acting at kidney to feedback repress CYP27B1 and induce CYP24A1 to limit the levels of 1,25D. In 3T3-L1 differentiated adipocytes, 1,25D represses FGF23 and leptin expression and induces C/EBPβ, but does not affect leptin receptor transcription. Conversely, in UMR-106 osteoblast-like cells, FGF23 mRNA concentrations are upregulated by 1,25D, an effect that is blunted by lysophosphatidic acid, a cell-surface acting ligand. Progressive truncation of the mouse FGF23 proximal promoter linked in luciferase reporter constructs reveals a 1,25D-responsive region between -400 and -200  bp. A 0.6  kb fragment of the mouse FGF23 promoter, linked in a reporter construct, responds to 1,25D with a fourfold enhancement of transcription in transfected K562 cells. Mutation of either an ETS1 site at -346  bp, or an adjacent candidate vitamin D receptor (VDR)/Nurr1-element, in the 0.6  kb reporter construct reduces the transcriptional activity elicited by 1,25D to a level that is not significantly different from a minimal promoter. This composite ETS1-VDR/Nurr1 cis-element may function as a switch between induction (osteocytes) and repression (adipocytes) of FGF23, depending on the cellular setting of transcription factors. Moreover, experiments demonstrate that a 1 kb mouse FGF23 promoter-reporter construct, transfected into MC3T3-E1 osteoblast-like cells, responds to a high calcium challenge with a statistically significant 1.7- to 2.0-fold enhancement of transcription. Thus, the FGF23 proximal promoter harbors cis elements that drive responsiveness to 1,25D and calcium, agents that induce FGF23 to curtail the pathologic consequences of their excess.
authors.affiliation: Department of Basic Medical SciencesUniversity of Arizona College of Medicine, 425 N. Fifth Street, Phoenix, Arizona 85004, USASchool of Mathematical and Natural SciencesArizona State University, 4701 W. Thunderbird Road, Phoenix, Arizona 85306, USA Department of Basic Medical SciencesUniversity of Arizona College of Medicine, 425 N. Fifth Street, Phoenix, Arizona 85004, USASchool of Mathematical and Natural SciencesArizona State University, 4701 W. Thunderbird Road, Phoenix, Arizona 85306, USA.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Kaneko
authors.affiliation: Department of Basic Medical SciencesUniversity of Arizona College of Medicine, 425 N. Fifth Street, Phoenix, Arizona 85004, USASchool of Mathematical and Natural SciencesArizona State University, 4701 W. Thunderbird Road, Phoenix, Arizona 85306, USA.
authors.forename: Rimpi K
authors.initials: RK
authors.lastname: Saini
authors.affiliation: Department of Basic Medical SciencesUniversity of Arizona College of Medicine, 425 N. Fifth Street, Phoenix, Arizona 85004, USASchool of Mathematical and Natural SciencesArizona State University, 4701 W. Thunderbird Road, Phoenix, Arizona 85306, USA.
authors.forename: Kristin P
authors.initials: KP
authors.lastname: Griffin
authors.affiliation: Department of Basic Medical SciencesUniversity of Arizona College of Medicine, 425 N. Fifth Street, Phoenix, Arizona 85004, USASchool of Mathematical and Natural SciencesArizona State University, 4701 W. Thunderbird Road, Phoenix, Arizona 85306, USA.
authors.forename: G Kerr
authors.initials: GK
authors.lastname: Whitfield
authors.affiliation: Department of Basic Medical SciencesUniversity of Arizona College of Medicine, 425 N. Fifth Street, Phoenix, Arizona 85004, USASchool of Mathematical and Natural SciencesArizona State University, 4701 W. Thunderbird Road, Phoenix, Arizona 85306, USA.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Haussler
authors.affiliation: Department of Basic Medical SciencesUniversity of Arizona College of Medicine, 425 N. Fifth Street, Phoenix, Arizona 85004, USASchool of Mathematical and Natural SciencesArizona State University, 4701 W. Thunderbird Road, Phoenix, Arizona 85306, USA Department of Basic Medical SciencesUniversity of Arizona College of Medicine, 425 N. Fifth Street, Phoenix, Arizona 85004, USASchool of Mathematical and Natural SciencesArizona State University, 4701 W. Thunderbird Road, Phoenix, Arizona 85306, USA pjurutka@asu.edu.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Jurutka
mesh_terms: D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D008246:Lysophospholipids / Q000494:pharmacology; D051379:Mice; D010011:Osteocytes / Q000187:drug effects* / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051381:Rats; D015854:Up-Regulation / Q000187:drug effects; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C000717428:Fgf23 protein, mouse; D008246:Lysophospholipids; D014807:Vitamin D; D005346:Fibroblast Growth Factors; C097949:1,25-dihydroxyvitamin D; D000089703:Fibroblast Growth Factor-23; C032881:lysophosphatidic acid
keywords: adipose; gene regulation; hormone receptors; transcription factors; vitamin D