Osteoblast Autonomous Pi Regulation via Pit1 Plays a Role in Bone Mineralization
Osteoblast Autonomous Pi Regulation via Pit1 Plays a Role in Bone Mineralization
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DOI：
10.1128/mcb.00104-07
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发表时间：
2007-04
影响因子：
5.3
通讯作者：
Yuji Yoshiko;Yuji Yoshiko;G. Candeliere;N. Maeda;J. Aubin
中科院分区：
文献类型：
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作者：
Yuji Yoshiko;Yuji Yoshiko;G. Candeliere;N. Maeda;J. Aubin
摘要遗传性和/或获得性低磷酸盐血症疾病中所见的矿化缺陷的复杂发病机制表明，成骨细胞对局部无机磷酸盐（Pi）的调节可能是生理性骨矿化的限速步骤。为了测试成骨细胞自主磷酸盐调节系统是否调节矿化，我们操纵了完善的体内和体外模型，分别从成骨的细胞增殖/分化阶段研究矿化阶段。膦甲酸钠，一种NaPi转运的抑制剂，阻断成骨细胞培养物中类骨质形成的矿化和新生大鼠颅骨注射后的局部矿化。矿化也下调和上调，分别与下和过度表达的III型NaPi转运蛋白Pit 1在成骨细胞培养。在成骨细胞中表达的分子中，已知与Pi处理有关，斯钙素1被确定为膦甲酸治疗后的早期反应基因;它也受细胞外Pi的调节，并且本身增加了成骨细胞培养物和体内的Pit 1积累。这些结果为成骨细胞自主Pi处理在正常骨矿化中的功能作用和低磷酸盐血症疾病中骨骼组织中观察到的异常提供了新的见解。
ABSTRACT The complex pathogenesis of mineralization defects seen in inherited and/or acquired hypophosphatemic disorders suggests that local inorganic phosphate (Pi) regulation by osteoblasts may be a rate-limiting step in physiological bone mineralization. To test whether an osteoblast autonomous phosphate regulatory system regulates mineralization, we manipulated well-established in vivo and in vitro models to study mineralization stages separately from cellular proliferation/differentiation stages of osteogenesis. Foscarnet, an inhibitor of NaPi transport, blocked mineralization of osteoid formation in osteoblast cultures and local mineralization after injection over the calvariae of newborn rats. Mineralization was also down- and upregulated, respectively, with under- and overexpression of the type III NaPi transporter Pit1 in osteoblast cultures. Among molecules expressed in osteoblasts and known to be related to Pi handling, stanniocalcin 1 was identified as an early response gene after foscarnet treatment; it was also regulated by extracellular Pi, and itself increased Pit1 accumulation in both osteoblast cultures and in vivo. These results provide new insights into the functional role of osteoblast autonomous Pi handling in normal bone mineralization and the abnormalities seen in skeletal tissue in hypophosphatemic disorders.