Basic research for phosphaturic factors including FGF23 as molecular targets for clinical applications.

遗传性和/或获得性低磷血症中矿化缺陷的复杂发病机制表明，成骨细胞对局部磷酸盐(PI)的调节以及包括成纤维细胞生长因子(FGF23)在内的PI调节因子可能是生理性骨矿化的限速步骤。通过使用多只大鼠模型，我们建立了以下结果。本研究的主要研究内容如下：1.我们采用了成熟的体内和体外模型，分别从成骨的细胞增殖/分化阶段来研究骨矿化阶段。成骨细胞中的钠依赖磷酸(Napi)共转运蛋白对于骨矿化是至关重要的。在已鉴定的多种钠依赖的PI(NaN)共转运子中，成骨细胞培养中的骨矿化分别下调和上调，III型napi转运蛋白Pitl的表达分别下调和上调。FGF23在骨骼细胞和牙细胞中表达最丰富。我们使用腺病毒过表达系统在成骨细胞中过表达FGF23，导致依赖于成纤维细胞生长因子受体酪氨酸磷酸化的骨矿化缺陷。这些结果为了解成骨细胞PI调节因子在骨矿化中的作用提供了新的见解，其操作可能有助于治疗低磷血症和其他骨骼和牙齿疾病。

The complex pathogenesis of mineralization defects seen in inherited and/or acquired hypophosphatemic disorders suggests that local phosphate (Pi) regulation and Pi-regulating factors including fibroblast growth factor (FGF) 23 by osteoblasts may be a rate-limiting step in physiological bone mineralization. By using multiple rat models, we established following results.1. We manipulated well-established in vivo and in vitro models to study bone mineralization stages separately from cellular proliferation/differentiation stages of osteogenesis.2. Sodium-dependent phosphate (NaPi) cotransport in osteoblasts was crucial for bone mineralization by using foscarnet, a selecitive NaPi cotransporter independently of systemic Pi levels.3. Amongst multiple sodium-dependent Pi (Nan) cotranspoters identified, bone mineralization was down-and upregulated respectively with under- and overexpression of the type III NaPi transporter Pitl in osteoblast cultures.4. FGF23 was expressed most abundantly in skeletal cells and dental cells. We overexpressed FGF23 in osteoblasts by using the adenoviral overexpression system, resulting in bone mineralization defects dependently of tyrosine phosphorylation of FGF receptor.These results provide new insights into the functional role Pi-regulating factors of osteoblasts in bone mineralization, whose manipulations may be useful for hypophosphatemic and other skeletal and dental disorders.