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

无机磷酸盐（Pi）不仅在羟基磷灰石晶体形成中发挥作用，而且在软骨形成和破骨细胞骨吸收过程中作为多种细胞事件的信号分子，对骨骼发育至关重要。此外，遗传性和/或获得性低磷血症疾病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。在这些背景下，我们建立了以下结果：1。Foscarnet是一种钠依赖性Pi （NaPi）共转运抑制剂，在体内和体外阻断矿化，无全身副作用或对类骨形成的影响。在体外，III型钠依赖性Pi （NaPi）共转运蛋白Pit1的过表达和过表达也分别抑制或刺激矿化3。斯坦钙素1 （STC1）是一种已知的钙/磷酸盐调节分子，可以增加Pit1的积累和NaPi的摄取，从而加速体内和体外的矿化。STC1增加软骨细胞凋亡，同时增加Pi摄取，降低成纤维细胞生长因子23的表达。磷酸钙可逆转STC1对软骨细胞的作用。这些结果为成骨细胞和软骨细胞处理局部pi在正常骨骼发育中的功能作用以及在低磷血症疾病中骨骼组织中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.