Genetic dissection of phosphate- and vitamin D-mediated regulation of circulating Fgf23 concentrations

Xijie Yu, Yves Sabbagh, Siobhan I. Davis, Marie B. Demay, Kenneth E. White

Research output: Contribution to journalArticle

118 Scopus citations

Abstract

Fibroblast growth factor-23 (FGF23) is a circulating factor that plays critical roles in phosphate and vitamin D metabolism. The goal of our studies was to dissect the pathways directing the vitamin D-phosphate-FGF23 homeostatic axis. To test the role of diet in the regulation of Fgf23, wild-type (WT) mice were fed either a standard (0.44% phosphorus) or a low-phosphate (0.02%) diet. WT mice on standard diet had a serum phosphate of 9.5 ± 0.3 mg/dl and an Fgf23 concentration of 99.0 ± 10.6 pg/ml; mice on the low-phosphate diet had a phosphate of 5.0 ± 0.2 mg/dl (P < 0.01) and an Fgf23 of 10.6 ± 3.7 pg/ml (P < 0.01). To genetically separate the effects of phosphate and vitamin D on Fgf23, we examined vitamin D receptor null (VDR -/-) mice, which are hypocalcemic and hypophosphatemic secondary to hyperparathyroidism. On standard diets, WT and VDR+/- mice had Fgf23 levels of 106.0 ± 30.7 and 90.6 ± 17.3 pg/ml, respectively, whereas Fgf23 was undetectable in the VDR-/-. Animals were then placed on a diet that normalizes serum calcium and phosphorus. This 'rescue' increased Fgf23 in WT to 192.3 ± 32.5 pg/ml and in VDR+/- to 388.2 ± 89.6pg/ml, and importantly, in VDR-/- to 476.9 ± 60.1 pg/ml (P < 0.01 vs. WT). In addition, renal vitamin D 1-alpha hydroxylase (1α-OHase) mRNA levels were corrected to WT levels in the VDR-/- mice. In summary, Fgf23 is suppressed in diet-induced hypophosphatemia and in hypophosphatemia associated with secondary hyperparathyroidism. Normalization of serum phosphate by diet in VDR -/- mice increases Fgf23. Thus, our results demonstrate that Fgf23 is independently regulated by phosphate and by vitamin D.

Original languageEnglish (US)
Pages (from-to)971-977
Number of pages7
JournalBone
Volume36
Issue number6
DOIs
StatePublished - Jun 1 2005

Keywords

  • 1-alpha-hydroxylase
  • Fgf23
  • Hypophosphatemia
  • Npt2a
  • VDR
  • Vitamin D receptor

ASJC Scopus subject areas

  • Physiology
  • Hematology

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