title: Homozygous ablation of fibroblast growth factor-23 results in hyperphosphatemia and impaired skeletogenesis, and reverses hypophosphatemia in Phex-deficient mice.
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.
authors.affiliation: Department of Oral and Developmental Biology, The Forsyth Institute, Harvard School of Dental Medicine, 140 The Fenway, Boston, MA, 02115, USA.
authors.forename: Despina
authors.initials: D
authors.lastname: Sitara
authors.forename: Mohammed S
authors.initials: MS
authors.lastname: Razzaque
authors.forename: Martina
authors.initials: M
authors.lastname: Hesse
authors.forename: Subbiah
authors.initials: S
authors.lastname: Yoganathan
authors.forename: Takashi
authors.initials: T
authors.lastname: Taguchi
authors.forename: Reinhold G
authors.initials: RG
authors.lastname: Erben
authors.forename: Harald
authors.initials: H
authors.lastname: Jüppner
authors.forename: Beate
authors.initials: B
authors.lastname: Lanske
mesh_terms: D000483:Alleles; D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology; D015139:Blotting, Southern; D001842:Bone and Bones / Q000378:metabolism*; D049109:Cell Proliferation; D041321:Chromosomes, Human, X / Q000235:genetics; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000502:physiology*; D008040:Genetic Linkage; D006720:Homozygote; D006801:Humans; D017674:Hypophosphatemia / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D017403:In Situ Hybridization; D007763:Lac Operon; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008957:Models, Genetic; D009154:Mutation; D010018:Osteomalacia / Q000097:blood; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; D010710:Phosphates / Q000737:chemistry / Q000378:metabolism; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D014965:X-Rays
chemical_list: D000880:Anthraquinones; C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D010710:Phosphates; D011506:Proteins; D012333:RNA, Messenger; C010078:alizarin; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D053402:PHEX Phosphate Regulating Neutral Endopeptidase; C506231:PHEX protein, human; C506232:Phex protein, mouse