FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis.
We analyzed the effects of an FGF-23 injection in vivo. FGF-23 caused a reduction in serum 1,25-dihydroxyvitamin D by altering the expressions of key enzymes for the vitamin D metabolism followed by hypophosphatemia. This study indicates that FGF-23 is a potent regulator of the vitamin D and phosphate metabolism.


BACKGROUND
The pathophysiological contribution of FGF-23 in hypophosphatemic diseases was supported by animal studies in which the long-term administration of recombinant fibroblast growth factor-23 reproduced hypophosphatemic rickets with a low serum 1,25-dihydroxyvitamin D [1,25(OH)2D] level. However, there is no clear understanding of how FGF-23 causes these changes.


METHODS
To elucidate the molecular mechanisms of the FGF-23 function, we investigated the short-term effects of a single administration of recombinant FGF-23 in normal and parathyroidectmized animals.


RESULTS
An injection of recombinant FGF-23 caused a reduction in serum phosphate and 1,25(OH)2D levels. A decrease in serum phosphate was first observed 9 h after the injection and was accompanied with a reduction in renal mRNA and protein levels for the type IIa sodium-phosphate cotransporter (NaPi-2a). There was no increase in the parathyroid hormone (PTH) level throughout the experiment, and hypophosphatemia was reproduced by FGF-23 in parathyroidectomized rats. Before this hypophosphatemic effect, the serum 1,25(OH)2D level had already descended at 3 h and reached the nadir 9 h after the administration. FGF-23 reduced renal mRNA for 25-hydroxyvitamin D-1alpha-hydroxylase and increased that for 25-hydroxyvitamin D-24-hydroxylase starting at 1 h. In addition, an injection of calcitriol into normal mice increased the serum FGF-23 level within 4 h.


CONCLUSIONS
FGF-23 regulates NaPi-2a independently of PTH and the serum 1,25(OH)2D level by controlling renal expressions of key enzymes of the vitamin D metabolism. In conclusion, FGF-23 is a potent regulator of phosphate and vitamin D homeostasis.
Shimada
Takashi
T
Pharmaceutical Research Laboratories, KIRIN Brewery Co., Ltd., Takasaki, Gumma, Japan. tyamashita@kirin.co.jp
Hasegawa
Hisashi
H
Yamazaki
Yuji
Y
Muto
Takanori
T
Hino
Rieko
R
Takeuchi
Yasuhiro
Y
Fujita
Toshiro
T
Nakahara
Kazuhiko
K
Fukumoto
Seiji
S
Yamashita
Takeyoshi
T
D000818:Animals; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000008:administration & dosage / Q000494:pharmacology*; D006706:Homeostasis / Q000502:physiology; D017674:Hypophosphatemia / Q000503:physiopathology; D008297:Male; D051379:Mice; D010710:Phosphates / Q000378:metabolism*; D051381:Rats; D011994:Recombinant Proteins / Q000008:administration & dosage; D013997:Time Factors; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism* / Q000652:urine
C000717428:Fgf23 protein, mouse; D010710:Phosphates; D011994:Recombinant Proteins; D014807:Vitamin D; D005346:Fibroblast Growth Factors; C097949:1,25-dihydroxyvitamin D; D000089703:Fibroblast Growth Factor-23