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）的调节和Pi调节因子（包括成纤维细胞生长因子（FGF） 23）可能是生理性骨矿化的限速步骤。通过使用多种大鼠模型，我们建立了以下结果：我们利用成熟的体内和体外模型分别研究骨矿化阶段和成骨细胞增殖/分化阶段。钠依赖性磷酸盐（NaPi）在成骨细胞中的共转运对骨矿化至关重要，它是一种独立于全身Pi水平的选择性NaPi共转运体。在鉴定的多个钠依赖性Pi （Nan）协转座子中，骨矿化分别随着III型NaPi转运体Pitl的过表达和过表达而下调和上调。FGF23在骨细胞和牙细胞中表达最丰富。我们利用腺病毒过表达系统在成骨细胞中过表达FGF23，导致骨矿化缺陷依赖于FGF受体酪氨酸磷酸化。这些结果为成骨细胞pi调节因子在骨矿化中的功能作用提供了新的见解，其操作可能对低磷血症和其他骨骼和牙齿疾病有用。

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.