1,25-Dihydroxyvitamin D3 regulation of fibroblast growth factor-23 expression in bone cells: Evidence for primary and secondary mechanisms modulated by leptin and interleukin-6

Rimpi K. Saini, Ichiro Kaneko, Peter Jurutka, Ryan Forster, Antony Hsieh, Jui Cheng Hsieh, Mark R. Haussler, G. Kerr Whitfield

Research output: Contribution to journalArticle

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Abstract

Fibroblast growth factor-23 (FGF23) is a circulating hormone that acts to correct hyperphosphatemic states by inhibiting renal phosphate reabsorption and to prevent hypervitaminosis D by feedback repressing 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) biosynthesis. FGF23 gene expression in the osteoblast/osteocyte is induced by the nuclear vitamin D receptor (VDR) bound to 1,25(OH)2D3, but cycloheximide sensitivity of this induction suggests that it may occur largely via secondary mechanisms requiring cooperating transcription factors. We therefore sought to identify 1,25(OH)2D3-regulated transcription factors that might impact FGF23 expression. Although neither leptin nor interleukin-6 (IL-6) alone affects FGF23 expression, leptin treatment was found to potentiate 1,25(OH)2D3 upregulation of FGF23 in UMR-106 cells, whereas IL-6 treatment blunted this upregulation. Genomic analyses revealed conserved binding sites for STATs (signal transduction mediators of leptin and IL-6 action) along with transcription factor ETS1 in human and other mammalian FGF23 genes. Further, STAT3, STAT1, ETS1, and VDR mRNAs were induced in a dose-dependent manner by 1,25(OH)2D3 in UMR-106 cells. Bioinformatic analysis identified nine potential VDREs in a genomic interval containing human FGF23. Six of the putative VDREs were capable of mediating direct transcriptional activation of a heterologous reporter gene when bound by a 1,25(OH)2D3-liganded VDR complex. A model is proposed wherein 1,25(OH)2D3 upregulates FGF23 production directly via multiple VDREs and indirectly via induction of STAT3, ETS1, and VDR transcription factors that are then activated via cell surface and intracellular signaling to cooperate in the induction of FGF23 through DNA looping and generation of euchromatin architecture.

Original languageEnglish (US)
Pages (from-to)339-353
Number of pages15
JournalCalcified Tissue International
Volume92
Issue number4
DOIs
StatePublished - Apr 2013

Fingerprint

Calcitriol
Leptin
Interleukin-6
Bone and Bones
Calcitriol Receptors
Transcription Factors
Up-Regulation
Euchromatin
fibroblast growth factor 23
Osteocytes
Cycloheximide
Computational Biology
Osteoblasts
Reporter Genes
Transcriptional Activation
Signal Transduction
Phosphates
Binding Sites
Hormones
Gene Expression

Keywords

  • 1,25-Dihydroxyvitamin D
  • ETS1
  • Fibroblast growth factor-23
  • Hormone responsive elements
  • STAT1
  • Vitamin D receptor

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

Cite this

1,25-Dihydroxyvitamin D3 regulation of fibroblast growth factor-23 expression in bone cells : Evidence for primary and secondary mechanisms modulated by leptin and interleukin-6. / Saini, Rimpi K.; Kaneko, Ichiro; Jurutka, Peter; Forster, Ryan; Hsieh, Antony; Hsieh, Jui Cheng; Haussler, Mark R.; Whitfield, G. Kerr.

In: Calcified Tissue International, Vol. 92, No. 4, 04.2013, p. 339-353.

Research output: Contribution to journalArticle

Saini, Rimpi K. ; Kaneko, Ichiro ; Jurutka, Peter ; Forster, Ryan ; Hsieh, Antony ; Hsieh, Jui Cheng ; Haussler, Mark R. ; Whitfield, G. Kerr. / 1,25-Dihydroxyvitamin D3 regulation of fibroblast growth factor-23 expression in bone cells : Evidence for primary and secondary mechanisms modulated by leptin and interleukin-6. In: Calcified Tissue International. 2013 ; Vol. 92, No. 4. pp. 339-353.
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