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.