A basic study on FGF23 for molecular targeted therapy of bone/tooth diseases

成纤维细胞生长因子23（Fibroblast growth factor 23，FGF 23）在1α，25-二羟维生素D_3（1，25（OH）_2D_3）刺激下，以磷酸尿激素的形式发挥作用，并将肾脏中FGF 23的辅助受体Klotho的截短型（sKL）释放到循环中。在这里，我们发现，静脉注射sKL迅速增加ERK磷酸化作为FGF 23信号在骨，但不是在肾脏中的小鼠，当预装1，25（OH）_2D_3。在Klotho缺陷突变（kl/kl）小鼠中模拟了骨中sKL的独特活性，尽管kl/kl的磷酸盐、钙、1，25（OH）_2D_3和FGF 23的血清浓度高。这些小鼠表现出选择性积聚的FGF 23和sKL和随后的低矿化顶骨，没有变化的血清参数检查。当FGF 23水平增加1，25（OH）_2D_3时，血清中的sKL对于与FGF 23的复合物形成以及成骨细胞/骨细胞培养物中相应的低矿化作用是必需的。这些数据定义了一种新的骨-肾轴，其中sKL作为顶骨中FGF 23的辅因子，独特的骨环境介导FGF 23的局部作用。

Fibroblast growth factor 23 (FGF23) acts as a phosphaturic hormone upon 1α, 25-dihydroxyvitamin D_3 (1,25(OH)_2D_3) stimulation, and the truncated form (sKL) of Klotho, a coreceptor for FGF23 in kidney, is released into the circulation. Here, we show that an intravenous injection of sKL rapidly increases ERK phosphorylation as FGF23 signaling in bone but not in kidney in mice, when preloaded with 1,25(OH)_2D_3. The unique activity of sKL in bone is mimicked in Klotho-deficient mutant (kl/kl) mice, in spite of the kl/kl high serum concentrations of phosphate, calcium, 1,25(OH)_2D_3 and FGF23. These mice exhibit selective accumulation of FGF23 and sKL and subsequent hypomineralization in parietal bone, without changes in serum parameters examined. sKL in serum is necessary for complex formation with FGF23 and the corresponding hypomineralization effects in osteoblast/osteocyte cultures, when FGF23 levels are increased by 1,25(OH)_2D_3. These data define a novel bone-kidney axis in which sKL acts as a cofactor for FGF23 in parietal bone, and the unique bone milieu mediates the local actions of FGF23.