Osteopontin negatively regulates parathyroid hormone receptor signaling in osteoblasts
Osteopontin negatively regulates parathyroid hormone receptor signaling in osteoblasts
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DOI：
10.1074/jbc.m800005200
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发表时间：
2008-07-11
影响因子：
4.8
通讯作者：
Noda, Masaki
中科院分区：
文献类型：
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作者：
Ono, Noriaki;Nakashima, Kazuhisa;Noda, Masaki
全身激素控制通过调控局部靶组织发挥作用，而局部靶组织又在一个反馈回路中调控上游信号。甲状旁腺激素（PTH）轴是一个明确的激素信号系统，调节钙水平和骨代谢。为了了解骨系统和局部信号之间的相互作用，我们研究了骨基质蛋白骨桥蛋白（OPN）缺乏对成骨细胞谱系中PTH系统效应的影响。甲状旁腺激素受体（PPR）转基因小鼠在成骨细胞谱系中特异性表达一种组成型活性受体（caPPR），具有高骨量表型。在这些小鼠中，OPN缺乏进一步增加了骨量。这种增加与主要的骨小梁间细胞群从造血细胞转化为基质/成骨细胞以及骨形成和骨吸收的组织形态计量学和生化参数的平行升高有关。用小干扰RNA （siRNA）处理骨桥蛋白可使H223R突变体cappr诱导的camp反应元件（CRE）活性水平提高约10倍。因此，除了众所周知的PTH钙反馈系统外，骨基质蛋白OPN的局部反馈调节在PTH的作用中也起着重要作用。
Systemic hormonal control exerts its effect through the regulation of local target tissues, which in turn regulate upstream signals in a feedback loop. The parathyroid hormone (PTH) axis is a well defined hormonal signaling system that regulates calcium levels and bone metabolism. To understand the interplay between systemic and local signaling in bone, we examined the effects of deficiency of the bone matrix protein osteopontin (OPN) on the systemic effects of PTH specifically within osteoblastic cell lineages. Parathyroid hormone receptor (PPR) transgenic mice expressing a constitutively active form of the receptor (caPPR) specifically in cells of the osteoblast lineage have a high bone mass phenotype. In these mice, OPN deficiency further increased bone mass. This increase was associated with conversion of the major intertrabecular cell population from hematopoietic cells to stromal/osteoblastic cells and parallel elevations in histomorphometric and biochemical parameters of bone formation and resorption. Treatment with small interfering RNA (siRNA) for osteopontin enhanced H223R mutant caPPR-induced cAMP-response element (CRE) activity levels by about 10-fold. Thus, in addition to the well known calcemic feedback system for PTH, local feedback regulation by the bone matrix protein OPN also plays a significant role in the regulation of PTH actions.