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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.

在遗传性和/或获得性低磷酸盐血症疾病中观察到的矿化缺陷的复杂发病机制表明，成骨细胞的局部磷酸盐（Pi）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。通过多种大鼠模型的建立，我们得到以下结果.本研究采用成熟的体内和体外模型，将骨矿化阶段与成骨细胞增殖/分化阶段分开研究.通过使用膦甲酸（一种不依赖于系统Pi水平的选择性NaPi共转运蛋白），成骨细胞中的钠依赖性磷酸盐（NaPi）共转运对骨矿化至关重要.在鉴定的多种钠依赖性Pi（Nan）共转运体中，在成骨细胞培养物中，骨矿化分别随着III型NaPi转运体Pitl的不足和过度表达而下调和上调。FGF 23在骨骼肌细胞和牙源性细胞中表达最丰富。我们利用腺病毒过表达系统在成骨细胞中过表达FGF 23，导致依赖于FGF受体酪氨酸磷酸化的骨矿化缺陷，这些结果为成骨细胞中PI调节因子在骨矿化中的功能作用提供了新的见解，其操作可能对低磷酸盐血症和其他骨骼和牙齿疾病有用。