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(American Journal of Pathology. 2006;169:2161-2170.)
© 2006 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2006.060329

Genetic Ablation of Vitamin D Activation Pathway Reverses Biochemical and Skeletal Anomalies in Fgf-23-Null Animals

Despina Sitara^*, Mohammed S. Razzaque^*, René St-Arnaud, Wei Huang^*, Takashi Taguchi, Reinhold G. Erben and Beate Lanske^*

From the Department of Developmental Biology,^* Harvard School of Dental Medicine, Boston, Massachusetts; the Genetics Unit, Shriners Hospital, Montreal, Quebec, Canada; the Department of Pathology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan; and the Department of Natural Sciences, University of Veterinary Medicine, Vienna, Austria

Fibroblast growth factor-23 (FGF-23) is one of the circulating phosphaturic factors associated with renal phosphate wasting. Fgf-23^–/– animals show extremely high serum levels of phosphate and 1,25-dihydroxyvitamin D₃, along with abnormal bone mineralization and soft tissue calcifications. To determine the role of vitamin D in mediating altered phosphate homeostasis and skeletogenesis in the Fgf-23^–/– mice, we generated mice lacking both the Fgf-23 and 1-hydroxylase genes (Fgf-23^–/–/1(OH)ase^–/–). In the current study, we have identified the cellular source of Fgf-23 in adult mice. In addition, loss of vitamin D activities from Fgf-23^–/– mice reverses the severe hyperphosphatemia to hypophosphatemia, attributable to increased urinary phosphate wasting in Fgf-23^–/–/1(OH)ase^–/– mice, possibly as a consequence of decreased expression of NaPi2a. Ablation of vitamin D from Fgf-23^–/– mice resulted in further reduction of total bone mineral content and bone mineral density and reversed ectopic calcification of skeleton and soft tissues, suggesting that abnormal mineral ion homeostasis and impaired skeletogenesis in Fgf-23^–/– mice are mediated through enhanced vitamin D activities. In conclusion, using genetic manipulation studies, we have provided evidence for an in vivo inverse correlation between Fgf-23 and vitamin D activities and for the severe skeletal and soft tissue abnormalities of Fgf-23^–/– mice being mediated through vitamin D.

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