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

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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.