Genetic dissection of phosphate- and vitamin D-mediated regulation of circulating Fgf23 concentrations.
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 (1alpha-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.
Yu
Xijie
X
Department of Medical and Molecular Genetics, 975 West Walnut Street, IB130, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Sabbagh
Yves
Y
Davis
Siobhan I
SI
Demay
Marie B
MB
White
Kenneth E
KE
D000818:Animals; D002118:Calcium / Q000097:blood / Q000494:pharmacology; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood* / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D007014:Hypophosphatasia / Q000097:blood / Q000378:metabolism; D007785:Lactose / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010710:Phosphates / Q000378:metabolism / Q000502:physiology*; D010758:Phosphorus / Q000097:blood / Q000172:deficiency; D016226:Phosphorus, Dietary / Q000008:administration & dosage / Q000097:blood; D018167:Receptors, Calcitriol / Q000235:genetics; D013250:Steroid Hydroxylases / Q000235:genetics; D014807:Vitamin D / Q000378:metabolism / Q000502:physiology*
C000717428:Fgf23 protein, mouse; D010710:Phosphates; D016226:Phosphorus, Dietary; D018167:Receptors, Calcitriol; D014807:Vitamin D; D010758:Phosphorus; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D013250:Steroid Hydroxylases; C406322:vitamin D 1-alpha hydroxylase; D007785:Lactose; D002118:Calcium