Genetic dissection of phosphate- and vitamin D-mediated regulation of circulating Fgf23 concentrations

Xijie Yu, Yves Sabbagh, Siobhan I. Davis, Marie B. Demay, Kenneth White

Research output: Contribution to journalArticle

115 Citations (Scopus)

Abstract

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 (1α-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.

Original languageEnglish
Pages (from-to)971-977
Number of pages7
JournalBone
Volume36
Issue number6
DOIs
StatePublished - Jun 2005

Fingerprint

Vitamin D
Dissection
Phosphates
Diet
Hypophosphatemia
Calcitriol Receptors
Secondary Hyperparathyroidism
Phosphorus
Serum
Calcium
Kidney
Messenger RNA

Keywords

  • 1-alpha-hydroxylase
  • Fgf23
  • Hypophosphatemia
  • Npt2a
  • VDR
  • Vitamin D receptor

ASJC Scopus subject areas

  • Physiology
  • Hematology

Cite this

Genetic dissection of phosphate- and vitamin D-mediated regulation of circulating Fgf23 concentrations. / Yu, Xijie; Sabbagh, Yves; Davis, Siobhan I.; Demay, Marie B.; White, Kenneth.

In: Bone, Vol. 36, No. 6, 06.2005, p. 971-977.

Research output: Contribution to journalArticle

Yu, Xijie ; Sabbagh, Yves ; Davis, Siobhan I. ; Demay, Marie B. ; White, Kenneth. / Genetic dissection of phosphate- and vitamin D-mediated regulation of circulating Fgf23 concentrations. In: Bone. 2005 ; Vol. 36, No. 6. pp. 971-977.
@article{b841745fe19f449eac615948288c3b95,
title = "Genetic dissection of phosphate- and vitamin D-mediated regulation of circulating Fgf23 concentrations",
abstract = "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 (1α-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.",
keywords = "1-alpha-hydroxylase, Fgf23, Hypophosphatemia, Npt2a, VDR, Vitamin D receptor",
author = "Xijie Yu and Yves Sabbagh and Davis, {Siobhan I.} and Demay, {Marie B.} and Kenneth White",
year = "2005",
month = "6",
doi = "10.1016/j.bone.2005.03.002",
language = "English",
volume = "36",
pages = "971--977",
journal = "Bone",
issn = "8756-3282",
publisher = "Elsevier Inc.",
number = "6",

}

TY - JOUR

T1 - Genetic dissection of phosphate- and vitamin D-mediated regulation of circulating Fgf23 concentrations

AU - Yu, Xijie

AU - Sabbagh, Yves

AU - Davis, Siobhan I.

AU - Demay, Marie B.

AU - White, Kenneth

PY - 2005/6

Y1 - 2005/6

N2 - 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 (1α-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.

AB - 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 (1α-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.

KW - 1-alpha-hydroxylase

KW - Fgf23

KW - Hypophosphatemia

KW - Npt2a

KW - VDR

KW - Vitamin D receptor

UR - http://www.scopus.com/inward/record.url?scp=20444404265&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=20444404265&partnerID=8YFLogxK

U2 - 10.1016/j.bone.2005.03.002

DO - 10.1016/j.bone.2005.03.002

M3 - Article

C2 - 15869926

AN - SCOPUS:20444404265

VL - 36

SP - 971

EP - 977

JO - Bone

JF - Bone

SN - 8756-3282

IS - 6

ER -