Homozygous ablation of fibroblast growth factor-23 results in hyperphosphatemia and impaired skeletogenesis, and reverses hypophosphatemia in Phex-deficient mice

Despina Sitara, Mohammed S. Razzaque, Martina Hesse, Subbiah Yoganathan, Takashi Taguchi, Reinhold G. Erben, Harald Jüppner, Beate Lanske

Research output: Contribution to journalArticle

Abstract

Fibroblast growth factor-23 (FGF-23), a recently identified molecule that is mutated in patients with autosomal dominant hypophosphatemic rickets (ADHR), appears to be involved in the regulation of phosphate homeostasis. Although increased levels of circulating FGF-23 were detected in patients with different phosphate-wasting disorders such as oncogenic osteomalacia (OOM) and X-linked hypophosphatemia (XLH), it is not yet clear whether FGF-23 is directly responsible for the abnormal regulation of mineral ion homeostasis and consequently bone development. To address some of these unresolved questions, we generated a mouse model, in which the entire Fgf-23 gene was replaced with the lacZ gene. Fgf-23 null (Fgf-23 +IhI-/+IhI) mice showed signs of growth retardation by day 17, developed severe hyperphosphatemia with elevated serum 1,25(OH) 2D 3 levels, and died by 13 weeks of age. Hyperphosphatemia in Fgf-23 +IhI-/+IhI mice was accompanied by skeletal abnormalities, as demonstrated by histological, molecular, and various other morphometric analyses. Fgf-23 +IhI-/+IhI mice had increased total-body bone mineral content (BMC) but decreased bone mineral density (BMD) of the limbs. Overall, Fgf-23 +IhI-/+IhI mice exhibited increased mineralization, but also accumulation of unmineralized osteoid leading to marked limb deformities. Moreover, Fgf-23 +IhI-/+IhI mice showed excessive mineralization in soft tissues, including heart and kidney. To further expand our understanding regarding the role of Fgf-23 in phosphate homeostasis and skeletal mineralization, we crossed Fgf-23 +IhI-/+IhI animals with Hyp mice, the murine equivalent of XLH. Interestingly, Hyp males lacking both Fgf-23 alleles were indistinguishable from Fgf-23 +IhI-/+IhI mice, both in terms of serum phosphate levels and skeletal changes, suggesting that Fgf-23 is upstream of the phosphate regulating gene with homologies to endopeptidases on the X chromosome (Phex) and that the increased plasma Fgf-23 levels in Hyp mice (and in XLH patients) may be at least partially responsible for the phosphate imbalance in this disorder.

Original languageEnglish (US)
Pages (from-to)421-432
Number of pages12
JournalMatrix Biology
Volume23
Issue number7
DOIs
StatePublished - Nov 2004

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Hyperphosphatemia
Hypophosphatemia
Familial Hypophosphatemic Rickets
Phosphates
Homeostasis
Bone Density
Extremities
fibroblast growth factor 23
Endopeptidases
Lac Operon
Bone Development
X Chromosome
Serum
Genes
Minerals
Alleles
Ions
Kidney

Keywords

  • Bone
  • Fgf-23 null
  • Hyp
  • Mineralization
  • Phosphate

ASJC Scopus subject areas

  • Molecular Biology

Cite this

Homozygous ablation of fibroblast growth factor-23 results in hyperphosphatemia and impaired skeletogenesis, and reverses hypophosphatemia in Phex-deficient mice. / Sitara, Despina; Razzaque, Mohammed S.; Hesse, Martina; Yoganathan, Subbiah; Taguchi, Takashi; Erben, Reinhold G.; Jüppner, Harald; Lanske, Beate.

In: Matrix Biology, Vol. 23, No. 7, 11.2004, p. 421-432.

Research output: Contribution to journalArticle

Sitara, Despina ; Razzaque, Mohammed S. ; Hesse, Martina ; Yoganathan, Subbiah ; Taguchi, Takashi ; Erben, Reinhold G. ; Jüppner, Harald ; Lanske, Beate. / Homozygous ablation of fibroblast growth factor-23 results in hyperphosphatemia and impaired skeletogenesis, and reverses hypophosphatemia in Phex-deficient mice. In: Matrix Biology. 2004 ; Vol. 23, No. 7. pp. 421-432.
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