Role of the vitamin D receptor in FGF23 action on phosphate metabolism.
FGF23 (fibroblast growth factor 23) is a novel phosphaturic factor that influences vitamin D metabolism and renal re-absorption of Pi. The goal of the present study was to characterize the role of the VDR (vitamin D receptor) in FGF23 action using VDR(-/-) (VDR null) mice. Injection of FGF23M (naked DNA encoding the R179Q mutant of human FGF23) into VDR(-/-) and wildtype VDR(+/+) mice resulted in an elevation in serum FGF23 levels, but had no effect on serum calcium or parathyroid hormone levels. In contrast, injection of FGF23M resulted in significant decreases in serum Pi levels, renal Na/Pi co-transport activity and type II transporter protein levels in both groups when compared with controls injected with mock vector or with FGFWT (naked DNA encoding wild-type human FGF23). Injection of FGF23M resulted in a decrease in 25-hydroxyvitamin D 1a-hydroxylase mRNA levels in VDR(-/-) and VDR(+/+) mice, while 25-hydroxyvitamin D 24-hydroxylase mRNA levels were significantly increased in FGF23M-treated animals compared with mock vector control- or FGF23WT-treated animals. The degree of 24-hydroxylase induction by FGF23M was dependent on the VDR, since FGF23M significantly reduced the levels of serum 1,25(OH)2D3 [1,25-hydroxyvitamin D3] in VDR(+/+) mice, but not in VDR(-/-) mice. We conclude that FGF23 reduces renal Pi transport and 25-hydroxyvitamin D 1a-hydroxylase levels by a mechanism that is independent of the VDR. In contrast, the induction of 25-hydroxyvitamin D 24-hydroxylase and the reduction of serum 1,25(OH)2D3 levels induced by FGF23 are dependent on the VDR.
Inoue
Yoshio
Y
Department of Molecular Nutrition, Institute of Health Bioscience, The University of Tokushima Graduate School, Kuramoto-cho 3, Tokushima 770-8503, Japan.
Segawa
Hiroko
H
Kaneko
Ichiro
I
Yamanaka
Setsuko
S
Kusano
Kenichiro
K
Kawakami
Eri
E
Furutani
Junya
J
Ito
Mikiko
M
Kuwahata
Masashi
M
Saito
Hitoshi
H
Fukushima
Naoshi
N
Kato
Shigeaki
S
Kanayama
Hiro-Omi
HO
Miyamoto
Ken-ichi
K
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000502:physiology*; D005786:Gene Expression Regulation / Q000502:physiology; D007413:Intestinal Mucosa / Q000378:metabolism; D007668:Kidney / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010281:Parathyroid Hormone / Q000378:metabolism; D010758:Phosphorus / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000235:genetics / Q000502:physiology*; D050608:Sodium-Phosphate Cotransporter Proteins; D050610:Sodium-Phosphate Cotransporter Proteins, Type II; D013250:Steroid Hydroxylases / Q000378:metabolism; D027981:Symporters / Q000378:metabolism; D065668:Vitamin D3 24-Hydroxylase
C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D010281:Parathyroid Hormone; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D050608:Sodium-Phosphate Cotransporter Proteins; D050610:Sodium-Phosphate Cotransporter Proteins, Type II; D027981:Symporters; D010758:Phosphorus; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase; D002118:Calcium