Genetic ablation of vitamin D activation pathway reverses biochemical and skeletal anomalies in Fgf-23-null animals.
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 1alpha-hydroxylase genes (Fgf-23-/-/1alpha(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-/-/1alpha(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.
Sitara
Despina
D
Department of Developmental Biology, Harvard School of Dental Medicine, REB 303, 188 Longwood Ave., Boston, MA 02115, USA, and The Genetics Unit, Shriners Hospital, Montreal, Quebec, Canada.
Razzaque
Mohammed S
MS
St-Arnaud
René
R
Huang
Wei
W
Taguchi
Takashi
T
Erben
Reinhold G
RG
Lanske
Beate
B
D000818:Animals; D015519:Bone Density / Q000235:genetics; D001842:Bone and Bones / Q000002:abnormalities*; D002113:Calcification, Physiologic; D002118:Calcium / Q000097:blood / Q000652:urine; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics* / Q000378:metabolism; D015870:Gene Expression; D006614:Hindlimb / Q000000981:diagnostic imaging; D007668:Kidney / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D006899:Mixed Function Oxygenases / Q000235:genetics; D023421:Models, Animal; D010281:Parathyroid Hormone / Q000097:blood / Q000652:urine; D010710:Phosphates / Q000097:blood / Q000652:urine; D011859:Radiography; D015398:Signal Transduction; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa / Q000378:metabolism; D014807:Vitamin D / Q000235:genetics / Q000378:metabolism*
C000717428:Fgf23 protein, mouse; D010281:Parathyroid Hormone; D010710:Phosphates; C493555:Slc34a1 protein, mouse; D050613:Sodium-Phosphate Cotransporter Proteins, Type IIa; D014807:Vitamin D; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; D006899:Mixed Function Oxygenases; D002118:Calcium