Vitamin D receptor-independent FGF23 actions in regulating phosphate and vitamin D metabolism.
FGF23 suppresses both serum phosphate and 1,25-dihydroxyvitamin D [1,25D] levels in vivo. Because 1,25D itself is a potent regulator of phosphate metabolism, it has remained unclear whether FGF23-induced changes in phosphate metabolism were caused by a 1,25D-independent mechanism. To address this issue, we intravenously administered recombinant FGF23 to vitamin D receptor (VDR) null (KO) mice as a rapid bolus injection and evaluated the early effects of FGF23. Administration of recombinant FGF23 further decreased the serum phosphate level in VDR KO mice, accompanied by a reduction in renal sodium-phosphate cotransporter type IIa (NaPi2a) protein abundance and a reduced renal 25-hydroxyvitamin D-1alpha-hydroxylase (1alphaOHase) mRNA level. Thus FGF23-induced changes in NaPi2a and 1alphaOHase expression are independent of the 1,25D/VDR system. However, 24-hydroxylase (24OHase) mRNA expression remained undetectable by the treatment with FGF23. We also analyzed the regulatory mechanism for FGF23 expression. The serum FGF23 level was almost undetectable in VDR KO mice, whereas dietary calcium supplementation significantly increased circulatory levels of FGF23 and its mRNA abundance in bone. This finding indicates that calcium is another determinant of FGF23 production that occurs independently of the VDR-mediated mechanism. In contrast, dietary phosphate supplementation failed to induce FGF23 expression in the absence of VDR, whereas marked elevation in circulatory FGF23 was observed in wild-type mice fed with a high-phosphate diet. Taken together, FGF23 works, at least in part, in a VDR-independent manner, and FGF23 production is also regulated by multiple mechanisms involving VDR-independent pathways.
Shimada
Takashi
T
Pharmaceutical Research Laboratories, Kirin Brewery Co., Ltd., Takasaki, Gunma 370-1295, Japan.
Yamazaki
Yuji
Y
Takahashi
Motoo
M
Hasegawa
Hisashi
H
Urakawa
Itaru
I
Oshima
Takeshi
T
Ono
Kaori
K
Kakitani
Makoto
M
Tomizuka
Kazuma
K
Fujita
Toshiro
T
Fukumoto
Seiji
S
Yamashita
Takeyoshi
T
D000818:Animals; D002136:Calcium, Dietary; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000096:biosynthesis / Q000502:physiology*; D007262:Infusions, Intravenous; D051379:Mice; D018345:Mice, Knockout; D010710:Phosphates / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis; D018167:Receptors, Calcitriol / Q000235:genetics / Q000502:physiology*; D011994:Recombinant Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014807:Vitamin D / Q000378:metabolism*
D002136:Calcium, Dietary; C000717428:Fgf23 protein, mouse; D010710:Phosphates; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D011994:Recombinant Proteins; D014807:Vitamin D; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23