TY - JOUR
T1 - Genetic ablation of vitamin D activation pathway reverses biochemical and skeletal anomalies in Fgf-23-null animals
AU - Sitara, Despina
AU - Razzaque, Mohammed S.
AU - St-Arnaud, René
AU - Huang, Wei
AU - Taguchi, Takashi
AU - Erben, Reinhold G.
AU - Lanske, Beate
N1 - Funding Information:
Supported by funds from the Harvard School of Dental Medicine (to B.L.).
PY - 2006/12
Y1 - 2006/12
N2 - 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 D 3, 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 1α-hydroxylase genes (Fgf-23-/-/ 1α(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-/-/1α(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.
AB - 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 D 3, 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 1α-hydroxylase genes (Fgf-23-/-/ 1α(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-/-/1α(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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U2 - 10.2353/ajpath.2006.060329
DO - 10.2353/ajpath.2006.060329
M3 - Article
C2 - 17148678
AN - SCOPUS:34247545717
SN - 0002-9440
VL - 169
SP - 2161
EP - 2170
JO - American Journal of Pathology
JF - American Journal of Pathology
IS - 6
ER -