Genetic evidence of serum phosphate-independent functions of FGF-23 on bone

Despina Sitara, Somi Kim, Mohammed S. Razzaque, Clemens Bergwitz, Takashi Taguchi, Christiane Schüler, Reinhold G. Erben, Beate Lanske

Research output: Contribution to journalArticle

Abstract

Maintenance of physiologic phosphate balance is of crucial biological importance, as it is fundamental to cellular function, energy metabolism, and skeletal mineralization. Fibroblast growth factor-23 (FGF-23) is a master regulator of phosphate homeostasis, but the molecular mechanism of such regulation is not yet completely understood. Targeted disruption of the Fgf-23 gene in mice (Fgf-23-/-) elicits hyperphosphatemia, and an increase in renal sodium/phosphate co-transporter 2a (NaPi2a) protein abundance. To elucidate the pathophysiological role of augmented renal proximal tubular expression of NaPi2a in Fgf-23-/- mice and to examine serum phosphate-independent functions of Fgf23 in bone, we generated a new mouse line deficient in both Fgf-23 and NaPi2a genes, and determined the effect of genomic ablation of NaPi2a from Fgf-23-/- mice on phosphate homeostasis and skeletal mineralization. Fgf-23-/-/NaPi2a-/- double mutant mice are viable and exhibit normal physical activities when compared to Fgf-23-/- animals. Biochemical analyses show that ablation of NaPi2a from Fgf-23-/- mice reversed hyperphosphatemia to hypophosphatemia by 6 weeks of age. Surprisingly, despite the complete reversal of serum phosphate levels in Fgf-23-/-/NaPi2a-/-, their skeletal phenotype still resembles the one of Fgf23-/- animals. The results of this study provide the first genetic evidence of an in vivo pathologic role of NaPi2a in regulating abnormal phosphate homeostasis in Fgf-23-/- mice by deletion of both NaPi2a and Fgf-23 genes in the same animal. The persistence of the skeletal anomalies in double mutants suggests that Fgf-23 affects bone mineralization independently of systemic phosphate homeostasis. Finally, our data support (1) that regulation of phosphate homeostasis is a systemic effect of Fgf-23, while (2) skeletal mineralization and chondrocyte differentiation appear to be effects of Fgf-23 that are independent of phosphate homeostasis.

Original languageEnglish (US)
Article numbere1000154
JournalPLoS Genetics
Volume4
Issue number8
DOIs
StatePublished - Aug 2008

Fingerprint

fibroblast growth factors
serum
bone
Phosphates
phosphate
bones
phosphates
homeostasis
Bone and Bones
Homeostasis
Serum
mice
Hyperphosphatemia
mineralization
ablation
Sodium-Phosphate Cotransporter Proteins
gene
animal
Genes
Hypophosphatemia

ASJC Scopus subject areas

  • Genetics
  • Molecular Biology
  • Ecology, Evolution, Behavior and Systematics
  • Cancer Research
  • Genetics(clinical)

Cite this

Sitara, D., Kim, S., Razzaque, M. S., Bergwitz, C., Taguchi, T., Schüler, C., ... Lanske, B. (2008). Genetic evidence of serum phosphate-independent functions of FGF-23 on bone. PLoS Genetics, 4(8), [e1000154]. https://doi.org/10.1371/journal.pgen.1000154

Genetic evidence of serum phosphate-independent functions of FGF-23 on bone. / Sitara, Despina; Kim, Somi; Razzaque, Mohammed S.; Bergwitz, Clemens; Taguchi, Takashi; Schüler, Christiane; Erben, Reinhold G.; Lanske, Beate.

In: PLoS Genetics, Vol. 4, No. 8, e1000154, 08.2008.

Research output: Contribution to journalArticle

Sitara, D, Kim, S, Razzaque, MS, Bergwitz, C, Taguchi, T, Schüler, C, Erben, RG & Lanske, B 2008, 'Genetic evidence of serum phosphate-independent functions of FGF-23 on bone', PLoS Genetics, vol. 4, no. 8, e1000154. https://doi.org/10.1371/journal.pgen.1000154
Sitara, Despina ; Kim, Somi ; Razzaque, Mohammed S. ; Bergwitz, Clemens ; Taguchi, Takashi ; Schüler, Christiane ; Erben, Reinhold G. ; Lanske, Beate. / Genetic evidence of serum phosphate-independent functions of FGF-23 on bone. In: PLoS Genetics. 2008 ; Vol. 4, No. 8.
@article{34e69505294d4aeba44a3e81ecaa3170,
title = "Genetic evidence of serum phosphate-independent functions of FGF-23 on bone",
abstract = "Maintenance of physiologic phosphate balance is of crucial biological importance, as it is fundamental to cellular function, energy metabolism, and skeletal mineralization. Fibroblast growth factor-23 (FGF-23) is a master regulator of phosphate homeostasis, but the molecular mechanism of such regulation is not yet completely understood. Targeted disruption of the Fgf-23 gene in mice (Fgf-23-/-) elicits hyperphosphatemia, and an increase in renal sodium/phosphate co-transporter 2a (NaPi2a) protein abundance. To elucidate the pathophysiological role of augmented renal proximal tubular expression of NaPi2a in Fgf-23-/- mice and to examine serum phosphate-independent functions of Fgf23 in bone, we generated a new mouse line deficient in both Fgf-23 and NaPi2a genes, and determined the effect of genomic ablation of NaPi2a from Fgf-23-/- mice on phosphate homeostasis and skeletal mineralization. Fgf-23-/-/NaPi2a-/- double mutant mice are viable and exhibit normal physical activities when compared to Fgf-23-/- animals. Biochemical analyses show that ablation of NaPi2a from Fgf-23-/- mice reversed hyperphosphatemia to hypophosphatemia by 6 weeks of age. Surprisingly, despite the complete reversal of serum phosphate levels in Fgf-23-/-/NaPi2a-/-, their skeletal phenotype still resembles the one of Fgf23-/- animals. The results of this study provide the first genetic evidence of an in vivo pathologic role of NaPi2a in regulating abnormal phosphate homeostasis in Fgf-23-/- mice by deletion of both NaPi2a and Fgf-23 genes in the same animal. The persistence of the skeletal anomalies in double mutants suggests that Fgf-23 affects bone mineralization independently of systemic phosphate homeostasis. Finally, our data support (1) that regulation of phosphate homeostasis is a systemic effect of Fgf-23, while (2) skeletal mineralization and chondrocyte differentiation appear to be effects of Fgf-23 that are independent of phosphate homeostasis.",
author = "Despina Sitara and Somi Kim and Razzaque, {Mohammed S.} and Clemens Bergwitz and Takashi Taguchi and Christiane Sch{\"u}ler and Erben, {Reinhold G.} and Beate Lanske",
year = "2008",
month = "8",
doi = "10.1371/journal.pgen.1000154",
language = "English (US)",
volume = "4",
journal = "PLoS Genetics",
issn = "1553-7390",
publisher = "Public Library of Science",
number = "8",

}

TY - JOUR

T1 - Genetic evidence of serum phosphate-independent functions of FGF-23 on bone

AU - Sitara, Despina

AU - Kim, Somi

AU - Razzaque, Mohammed S.

AU - Bergwitz, Clemens

AU - Taguchi, Takashi

AU - Schüler, Christiane

AU - Erben, Reinhold G.

AU - Lanske, Beate

PY - 2008/8

Y1 - 2008/8

N2 - Maintenance of physiologic phosphate balance is of crucial biological importance, as it is fundamental to cellular function, energy metabolism, and skeletal mineralization. Fibroblast growth factor-23 (FGF-23) is a master regulator of phosphate homeostasis, but the molecular mechanism of such regulation is not yet completely understood. Targeted disruption of the Fgf-23 gene in mice (Fgf-23-/-) elicits hyperphosphatemia, and an increase in renal sodium/phosphate co-transporter 2a (NaPi2a) protein abundance. To elucidate the pathophysiological role of augmented renal proximal tubular expression of NaPi2a in Fgf-23-/- mice and to examine serum phosphate-independent functions of Fgf23 in bone, we generated a new mouse line deficient in both Fgf-23 and NaPi2a genes, and determined the effect of genomic ablation of NaPi2a from Fgf-23-/- mice on phosphate homeostasis and skeletal mineralization. Fgf-23-/-/NaPi2a-/- double mutant mice are viable and exhibit normal physical activities when compared to Fgf-23-/- animals. Biochemical analyses show that ablation of NaPi2a from Fgf-23-/- mice reversed hyperphosphatemia to hypophosphatemia by 6 weeks of age. Surprisingly, despite the complete reversal of serum phosphate levels in Fgf-23-/-/NaPi2a-/-, their skeletal phenotype still resembles the one of Fgf23-/- animals. The results of this study provide the first genetic evidence of an in vivo pathologic role of NaPi2a in regulating abnormal phosphate homeostasis in Fgf-23-/- mice by deletion of both NaPi2a and Fgf-23 genes in the same animal. The persistence of the skeletal anomalies in double mutants suggests that Fgf-23 affects bone mineralization independently of systemic phosphate homeostasis. Finally, our data support (1) that regulation of phosphate homeostasis is a systemic effect of Fgf-23, while (2) skeletal mineralization and chondrocyte differentiation appear to be effects of Fgf-23 that are independent of phosphate homeostasis.

AB - Maintenance of physiologic phosphate balance is of crucial biological importance, as it is fundamental to cellular function, energy metabolism, and skeletal mineralization. Fibroblast growth factor-23 (FGF-23) is a master regulator of phosphate homeostasis, but the molecular mechanism of such regulation is not yet completely understood. Targeted disruption of the Fgf-23 gene in mice (Fgf-23-/-) elicits hyperphosphatemia, and an increase in renal sodium/phosphate co-transporter 2a (NaPi2a) protein abundance. To elucidate the pathophysiological role of augmented renal proximal tubular expression of NaPi2a in Fgf-23-/- mice and to examine serum phosphate-independent functions of Fgf23 in bone, we generated a new mouse line deficient in both Fgf-23 and NaPi2a genes, and determined the effect of genomic ablation of NaPi2a from Fgf-23-/- mice on phosphate homeostasis and skeletal mineralization. Fgf-23-/-/NaPi2a-/- double mutant mice are viable and exhibit normal physical activities when compared to Fgf-23-/- animals. Biochemical analyses show that ablation of NaPi2a from Fgf-23-/- mice reversed hyperphosphatemia to hypophosphatemia by 6 weeks of age. Surprisingly, despite the complete reversal of serum phosphate levels in Fgf-23-/-/NaPi2a-/-, their skeletal phenotype still resembles the one of Fgf23-/- animals. The results of this study provide the first genetic evidence of an in vivo pathologic role of NaPi2a in regulating abnormal phosphate homeostasis in Fgf-23-/- mice by deletion of both NaPi2a and Fgf-23 genes in the same animal. The persistence of the skeletal anomalies in double mutants suggests that Fgf-23 affects bone mineralization independently of systemic phosphate homeostasis. Finally, our data support (1) that regulation of phosphate homeostasis is a systemic effect of Fgf-23, while (2) skeletal mineralization and chondrocyte differentiation appear to be effects of Fgf-23 that are independent of phosphate homeostasis.

UR - http://www.scopus.com/inward/record.url?scp=50849104780&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=50849104780&partnerID=8YFLogxK

U2 - 10.1371/journal.pgen.1000154

DO - 10.1371/journal.pgen.1000154

M3 - Article

C2 - 18688277

AN - SCOPUS:50849104780

VL - 4

JO - PLoS Genetics

JF - PLoS Genetics

SN - 1553-7390

IS - 8

M1 - e1000154

ER -