Dietary and serum phosphorus regulate fibroblast growth factor 23 expression and 1,25-dihydroxyvitamin D metabolism in mice.
Farzana Perwad,Nasreen Azam,Martin Y. H. Zhang,Takeyoshi Yamashita,Harriet S. Tenenhouse,Anthony A. Portale +5 more
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TLDR
It is demonstrated that dietary Pi regulates the serum FGF-23 concentration in mice, and such regulation is independent of phex function.Abstract:
Fibroblast growth factor-23 (FGF-23) is a novel circulating peptide that regulates phosphorus (Pi) and vitamin D metabolism, but the mechanisms by which circulating FGF-23 itself is regulated are unknown. To determine whether the serum FGF-23 concentration is regulated by dietary intake of Pi, we fed wild-type (WT), Npt2a gene-ablated (Npt2a(-/-)), and Hyp mice diets containing varying Pi contents (0.02-1.65%). In WT mice, increases in dietary Pi intake from 0.02-1.65% induced a 7-fold increase in serum FGF-23 and a 3-fold increase in serum Pi concentrations. Across the range of dietary Pi, serum FGF-23 concentrations varied directly with serum Pi concentrations (r(2) = 0.72; P < 0.001). In Npt2a(-/-) mice, serum FGF-23 concentrations were significantly lower than in WT mice, and these differences could be accounted for by the lower serum Pi levels in Npt2a(-/-) mice. The serum concentrations of FGF-23 in Hyp mice were 5- to 25-fold higher than values in WT mice, and the values varied with dietary Pi intake. Fgf-23 mRNA abundance in calvaria was significantly higher in Hyp mice than in WT mice on the 1% Pi diet; in both groups of mice, fgf-23 mRNA abundance in calvarial bone was suppressed by 85% on the low (0.02%) Pi diet. In WT mice fed the low (0.02%) Pi diet, renal mitochondrial 1alpha-hydroxylase activity and renal 1alpha-hydroxylase (P450c1alpha) mRNA abundance were significantly higher than in mice fed the higher Pi diets and varied inversely with serum FGF-23 concentrations (r(2) = 0.86 and r(2) = 0.64; P < 0.001, respectively). The present data demonstrate that dietary Pi regulates the serum FGF-23 concentration in mice, and such regulation is independent of phex function. The data suggest that genotype-dependent and dietary Pi-induced changes in the serum FGF-23 concentration reflect changes in fgf-23 gene expression in bone.read more
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References
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Journal ArticleDOI
FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis.
Takashi Shimada,Hisashi Hasegawa,Yuji Yamazaki,Takanori Muto,Rieko Hino,Yasuhiro Takeuchi,Toshiro Fujita,Kazuhiko Nakahara,Seiji Fukumoto,Takeyoshi Yamashita +9 more
TL;DR: FGF‐23 is a potent regulator of the vitamin D and phosphate metabolism and caused a reduction in serum 1,25‐dihydroxyvitamin D by altering the expressions of key enzymes for the vitaminD metabolism followed by hypophosphatemia.
Journal ArticleDOI
Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23
Kenneth E. White,Wayne E. Evans,Jeffery L.H. O'Riordan,Marcy C. Speer,Michael J. Econs,Bettina Lorenz-Depiereux,Bettina Lorenz-Depiereux,Monika Grabowski,Monika Grabowski,Thomas Meitinger,Thomas Meitinger,Tim M. Strom +11 more
TL;DR: A positional cloning approach was used to identify the ADHR gene which included the annotation of 37 genes within 4 Mb of genomic sequence, and missense mutations in a gene encoding a new member of the fibroblast growth factor (FGF) family, FGF23 were identified.
Journal ArticleDOI
Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism
Takashi Shimada,Makoto Kakitani,Yuji Yamazaki,Hisashi Hasegawa,Yasuhiro Takeuchi,Toshiro Fujita,Seiji Fukumoto,Kazuma Tomizuka,Takeyoshi Yamashita +8 more
TL;DR: Evidence is presented that FGF23 is a physiological regulator of serum phosphate and 1,25-dihydroxyvitamin D (1,25[OH]2D) by generating FGF 23-null mice, indicating that F GF23 is essential for normal phosphate and vitamin D metabolism.
Journal ArticleDOI
Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia
Takashi Shimada,Satoru Mizutani,Takanori Muto,Takashi Yoneya,Rieko Hino,Shu Takeda,Yasuhiro Takeuchi,Toshiro Fujita,Seiji Fukumoto,Takeyoshi Yamashita +9 more
TL;DR: It is concluded that overproduction of F GF23 causes TIO, whereas mutations in the FGF23 gene result in autosomal dominant hypophosphatemic rickets possibly by preventing proteolytic cleavage and enhancing biological activity of FGF 23.