Genetic ablation of vitamin D activation pathway reverses biochemical and skeletal anomalies in Fgf-23-null animals
Genetic ablation of vitamin D activation pathway reverses biochemical and skeletal anomalies in Fgf-23-null animals
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DOI：
10.2353/ajpath.2006.060329
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发表时间：
2006-12-01
影响因子：
6
通讯作者：
Lanske, Beate
中科院分区：
文献类型：
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作者：
Sitara, Despina;Razzaque, Mohammed S.;Lanske, Beate
成纤维细胞生长因子-23 (FGF-23) 是与肾磷酸盐消耗相关的循环磷酸盐因子之一。 Fgf-23(-/-) 动物表现出极高的血清磷酸盐和 1,25-二羟基维生素 D-3 水平，以及异常的骨矿化和软组织钙化。为了确定维生素 D 在调节 Fgf-23(-/-) 小鼠磷酸盐稳态和骨骼发生改变中的作用，我们培育了缺乏 Fgf-23 和 1α-羟化酶基因 (Fgf-23(-/-)/1 α(OH)ase(-/-)) 的小鼠。在当前的研究中，我们已经确定了成年小鼠中 Fgf-23 的细胞来源。此外，Fgf-23(-/-)小鼠维生素D活性的丧失可将严重的高磷血症逆转为低磷血症，这归因于Fgf-23(-/-)1 α(OH)ase(-/-)小鼠的尿磷酸盐消耗增加，这可能是NaPi2a表达减少的结果。 Fgf-23(-/-) 小鼠的维生素 D 消除导致总骨矿物质含量和骨矿物质密度进一步降低，并逆转骨骼和软组织的异位钙化，表明 Fgf-23(-/-) 小鼠中矿物质离子稳态异常和骨骼发生受损是通过增强维生素 D 活性介导的。总之，通过基因操作研究，我们提供了证据，证明 Fgf-23 和维生素 D 活性之间存在体内负相关性，并证明 Fgf-23(-/-) 小鼠的严重骨骼和软组织异常是通过维生素 D 介导的。
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 la-hydroxylase genes (Fgf-23(-/-)/1 alpha(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 inFgf-23(-/-)1 alpha(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.