Basic studies of a gene therapy approach for osteoblastic (odontoblastic) disability in inherited and tumor-induced hypophosphatemic disorders

针对遗传性和肿瘤引起的低磷血症疾病中成骨细胞（成牙本质细胞）残疾的基因治疗方法的基础研究

基本信息

批准号：
16591828
负责人：
YOSHIKO Yuji
金额：
$ 2.24万
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：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

项目摘要

Inorganic phosphate (Pi) is indispensable for skeletal development not only for its role in hydroxyapatite crystal formation but also as a signaling molecule for multiple cellular events during chondogenesis and osteoclastic bone resorption. Additionally, the complex pathogenesis of mineralization defects seen in inherited and/or acquired hypophosphatemic disorders suggests that local Pi regulation may contribute to osteoblast-mediated bone mineralization. In these backgrounds, we established following results :1.Foscarnet, an inhibitor of sodium-dependent Pi (NaPi) cotransport blocked mineralization in vivo and vitro without systemic side effects or effects on osteoid formation.2.Mineralization was also inhibited or stimulated respectively with under- and overexpression of the type III sodium-dependent Pi (NaPi) cotransporter Pit1 in vitro.3.Stanniocalcin 1 (STC1), a known calcium/phosphate regulating molecule, increased Pit1 accumulation and NaPi uptake, resulting in acceleration of mineralization in vivo and vitro.4.STC1 increased chondrocyte apoptosis concomitant with the increased Pi uptake and the decreased fibroblast growth factor 23 expression.5.The effects of STC1 on chondocytes were reversed by foscarnet.These results provide new insights into the functional role of local Pi-handling by osteoblasts and chondrocytes in normal skeletal development and the abnormalities seen in skeletal tissue in hypophosphatemic disorders.

无机磷酸盐（PI）对于骨骼发育是必不可少的，这不仅是其在羟基磷灰石晶体形成中的作用，而且还作为在软骨发生和整骨碎片骨吸收过程中多个细胞事件的信号分子。此外，在遗传和/或获得性下降磷酸盐疾病中看到的矿化缺陷的复杂发病机理表明，局部PI调控可能有助于成骨细胞介导的骨矿化。 In these backgrounds, we established following results :1.Foscarnet, an inhibitor of sodium-dependent Pi (NaPi) cotransport blocked mineralization in vivo and vitro without systemic side effects or effects on osteoid formation.2.Mineralization was also inhibited or stimulated respectively with under- and overexpression of the type III sodium-dependent Pi (NaPi) cotransporter Pit1 in vitro.3.Stanniocalcin 1 (STC1), a known calcium/phosphate regulating molecule, increased Pit1 accumulation and NaPi uptake, resulting in acceleration of mineralization in vivo and vitro.4.STC1 increased chondrocyte apoptosis concomitant with the increased Pi uptake and the decreased fibroblast growth factor 23 expression.5.The effects of STC1 on这些结果通过成骨细胞和软骨细胞在正常骨骼发育中的局部PI处理和骨骼组织中骨骼组织中的异常情况中的功能作用提供了新的见解。