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

无机磷(PI)不仅在羟基磷灰石晶体的形成中起着不可缺少的作用，而且在软骨形成和破骨细胞性骨吸收过程中也是多种细胞事件的信号分子。此外，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，局部PI调节可能有助于成骨细胞介导的骨矿化。在此背景下，我们建立了以下结果：1.磷甲酸钠，一种钠依赖PI(Napi)共转运的抑制剂，在体内和体外阻断矿化，没有全身副作用或对类骨质形成的影响。2.体外矿化也被抑制或刺激，而III型钠依赖PI(Napi)共转运体Pit1的低表达和过表达。3.已知的钙/磷调节分子stanniocalcin 1(STC1)增加了Pit1的积聚和napi的摄取。4.随着PI摄取的增加和成纤维细胞生长因子23表达的降低，STC1促进了软骨细胞的凋亡。5.STC1对软骨细胞的作用被磷灰石逆转。这些结果为了解成骨细胞和软骨细胞对PI的局部处理在正常骨骼发育中的功能作用以及在低磷性疾病中骨骼组织的异常提供了新的见解。

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.