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

以 FGF23 等磷酸盐因子为临床应用分子靶点的基础研究。

基本信息

批准号：
18592001
负责人：
YOSHIKO Yuji
金额：
$ 2.53万
依托单位：
Hiroshima University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2006
资助国家：
日本
起止时间：
2006 至 2007
项目状态：
已结题

项目摘要

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.

在遗传和/或获得性下降磷酸血症中看到的矿化缺陷的复杂发病机制表明，局部磷酸盐（PI）调节和PI-PI调节因子，包括成骨细胞成纤维细胞生长因子（FGF）23，可能是成骨细胞的，可能是生理骨矿化的速率限制步骤。通过使用多个大鼠模型，我们确定了以下结果1。我们操纵了良好的体内和体外模型，以研究骨矿化阶段，分别与细胞增殖/成骨的分化阶段分开。2。成骨细胞中钠依赖性磷酸盐（NAPI）共同体育对骨矿化至关重要，该骨矿化使用Foscarnet（一种对全身性PI级别独立于全身性PI级别）的foscarnet，foscarnet是骨矿化。3。在确定的多个依赖钠依赖性PI（NAN）共转载体中，骨矿化分别通过成骨细胞培养物中III NAPI型转运蛋白pitl的低音和过表达分别下调和上调。4。 FGF23在骨骼细胞和牙科细胞中表达最多。我们通过使用腺病毒过表达系统在成骨细胞中过表达FGF23，从而导致骨矿化缺陷依赖于FGF受体的酪氨酸磷酸化。这些结果对这些功能性作用的新见解提供了对骨骼矿物质中骨质矿物质的功能性作用的功能性作用，可用于骨骼矿物质和其他造成骨骼的procefticals promplations and prompoff shoreforcations and Spresportact。