Homozygous Ablation of Fibroblast Growth factor-23 Results in Hyperphosphatemia and Impaired Skeletogenesis, and Reverses Hypophosphatemia in Phex-deficient Mice

Matrix Biol. 2004 Nov;23(7):421-32. doi: 10.1016/j.matbio.2004.09.007.

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-/-) mice showed signs of growth retardation by day 17, developed severe hyperphosphatemia with elevated serum 1,25(OH)2D3 levels, and died by 13 weeks of age. Hyperphosphatemia in Fgf-23-/- mice was accompanied by skeletal abnormalities, as demonstrated by histological, molecular, and various other morphometric analyses. Fgf-23-/-) mice had increased total-body bone mineral content (BMC) but decreased bone mineral density (BMD) of the limbs. Overall, Fgf-23-/- mice exhibited increased mineralization, but also accumulation of unmineralized osteoid leading to marked limb deformities. Moreover, Fgf-23-/- 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-/- animals with Hyp mice, the murine equivalent of XLH. Interestingly, Hyp males lacking both Fgf-23 alleles were indistinguishable from Fgf-23/-/ 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alleles
  • Animals
  • Anthraquinones / pharmacology
  • Blotting, Southern
  • Bone and Bones / metabolism*
  • Cell Proliferation
  • Chromosomes, Human, X / genetics
  • Female
  • Fibroblast Growth Factors / genetics*
  • Fibroblast Growth Factors / physiology*
  • Genetic Linkage
  • Homozygote
  • Humans
  • Hypophosphatemia / blood
  • Hypophosphatemia / genetics*
  • Hypophosphatemia / metabolism
  • In Situ Hybridization
  • Lac Operon
  • Male
  • Mice
  • Mice, Transgenic
  • Models, Genetic
  • Mutation
  • Osteomalacia / blood
  • PHEX Phosphate Regulating Neutral Endopeptidase
  • Phosphates / chemistry
  • Phosphates / metabolism
  • Polymerase Chain Reaction
  • Promoter Regions, Genetic
  • Proteins / metabolism*
  • RNA, Messenger / metabolism
  • Time Factors
  • Tomography, X-Ray Computed
  • X-Rays

Substances

  • Anthraquinones
  • Phosphates
  • Proteins
  • RNA, Messenger
  • alizarin
  • Fibroblast Growth Factors
  • fibroblast growth factor 23
  • PHEX Phosphate Regulating Neutral Endopeptidase
  • PHEX protein, human
  • Phex protein, mouse