Fibroblast growth factor 23 is a counter-regulatory phosphaturic hormone for vitamin D

• Published in: Journal of the American Society of Nephrology 2006-05, Vol.17 (5), p.1305-1315
• Main Authors: SHIGUANG LIU, WEN TANG, JIANPING ZHOU, STUBBS, Jason R, QIANG LUO, MIN PI, DARRYL QUARLES, L
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Calcitriol - administration & dosage; Cells, Cultured; Dose-Response Relationship, Drug; Fibroblast Growth Factors - blood; Fibroblast Growth Factors - metabolism; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - drug effects; Gene Expression Regulation - physiology; Hemostasis - drug effects; Hemostasis - physiology; Hypophosphatemia - metabolism; Medical sciences; Mice; Mice, Inbred C57BL; Mice, Knockout; Nephrology. Urinary tract diseases; Osteoblasts - drug effects; Osteoblasts - metabolism; Phosphates - metabolism; Skeleton and joints; Vertebrates: osteoarticular system, musculoskeletal system
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1681/asn.2005111185

The regulation of the phosphaturic factor fibroblast growth factor 23 (FGF23) is not well understood. It was found that administration of 1,25-dihydroxyvitamin D(3) (1,25[OH](2)D(3)) to mice rapidly increased serum FGF23 concentrations from a basal level of 90.6 +/- 8.1 to 213.8 +/- 14.6 pg/ml at 8 h (mean +/- SEM; P < 0.01) and resulted in a four-fold increase in FGF23 transcripts in bone, the predominate site of FGF23 expression. In the Hyp-mouse homologue of X-linked hypophosphatemic rickets, administration of 1,25(OH)(2)D(3) further increased circulating FGF23 levels. In Gcm2 null mice, low 1,25(OH)(2)D(3) levels were associated with a three-fold reduction in FGF23 levels that were increased by administration of 1,25(OH)(2)D(3). In osteoblast cell cultures, 1,25(OH)(2)D(3) but not calcium, phosphate, or parathyroid hormone stimulated FGF23 mRNA levels and resulted in a dose-dependent increase in FGF23 promoter activity. Overexpression of a dominant negative vitamin D receptor inhibited 1,25(OH)(2)D(3) stimulation of FGF23 promoter activity, and mutagenesis of the FGF23 promoter identified a vitamin D-responsive element (-1180 GGAACTcagTAACCT -1156) that is responsible for the vitamin D effects. These data suggest that 1,25(OH)(2)D(3) is an important regulator of FGF23 production by osteoblasts in bone. The physiologic role of FGF23 may be to act as a counterregulatory phosphaturic hormone to maintain phosphate homeostasis in response to vitamin D.