FGF23 gene regulation by 1,25-dihyoxyvitamin D

Opposing effects in adipocytes and osteocytes

Ichiro Kaneko, Rimpi K. Saini, Kristin P. Griffin, G. Kerr Whitfield, Mark R. Haussler, Peter Jurutka

Research output: Contribution to journalArticle

20 Citations (Scopus)

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/EBPb, 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 K400 and K200 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 K346 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.

Original languageEnglish (US)
Pages (from-to)155-166
Number of pages12
JournalJournal of Endocrinology
Volume226
Issue number3
DOIs
StatePublished - 2015

Fingerprint

Osteocytes
Calcitriol
Adipocytes
Genes
Calcitriol Receptors
Osteoblasts
25-Hydroxyvitamin D3 1-alpha-Hydroxylase
Calcium
fibroblast growth factor 23
Leptin Receptors
K562 Cells
Leptin
Luciferases
Transcription Factors
Ligands
Kidney
Bone and Bones
Messenger RNA
Peptides
Mutation

Keywords

  • Adipose
  • Gene regulation
  • Hormone receptors
  • Transcription factors
  • Vitamin D

ASJC Scopus subject areas

  • Endocrinology
  • Endocrinology, Diabetes and Metabolism

Cite this

FGF23 gene regulation by 1,25-dihyoxyvitamin D : Opposing effects in adipocytes and osteocytes. / Kaneko, Ichiro; Saini, Rimpi K.; Griffin, Kristin P.; Whitfield, G. Kerr; Haussler, Mark R.; Jurutka, Peter.

In: Journal of Endocrinology, Vol. 226, No. 3, 2015, p. 155-166.

Research output: Contribution to journalArticle

Kaneko, Ichiro ; Saini, Rimpi K. ; Griffin, Kristin P. ; Whitfield, G. Kerr ; Haussler, Mark R. ; Jurutka, Peter. / FGF23 gene regulation by 1,25-dihyoxyvitamin D : Opposing effects in adipocytes and osteocytes. In: Journal of Endocrinology. 2015 ; Vol. 226, No. 3. pp. 155-166.
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AB - 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/EBPb, 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 K400 and K200 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 K346 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.

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