Sclerostin Mediates Bone Response to Mechanical Unloading Through Antagonizing Wnt/β-Catenin Signaling
Sclerostin Mediates Bone Response to Mechanical Unloading Through Antagonizing Wnt/β-Catenin Signaling
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DOI：
10.1359/jbmr.090411
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发表时间：
2009-10-01
影响因子：
6.2
通讯作者：
He, Lin
中科院分区：
文献类型：
--
作者：
Lin, Chuwen;Jiang, Xuan;He, Lin
减少机械应力会导致骨质流失，卧床不起的患者和宇航员的废用性骨质疏松症就是证明。骨细胞已被确定为负责机械转导的主要细胞;然而，骨对机械卸载的响应的机制仍然知之甚少。在这项研究中，我们发现野生型小鼠的机械卸载导致Wnt/β-catenin信号转导活性降低，伴随着Sost的上调。为了进一步分析这些事件之间的因果关系，产生了Sost基因靶向小鼠。我们发现sclerostin在体内选择性抑制Wnt/β-catenin，并且sclerostin抑制成骨细胞的活性以及成骨细胞和骨细胞的活力。有趣的是，Sost（-/-）小鼠对机械卸载诱导的骨丢失有抵抗力。在突变小鼠中，响应于卸载的骨形成减少也被消除。此外，与野生型小鼠相比，Sost（-/-）小鼠中的Wnt/β-连环蛋白信号转导未因卸载而改变。这些数据表明，sclerostin在介导骨对机械卸载的反应中发挥重要作用，可能是通过Wnt/β-连环蛋白信号传导。我们的研究结果也表明sclerostin是预防废用性骨质疏松症的一个有希望的靶点。骨矿研究杂志2009;24：1651-1661。在线发表于2009年4月27日; doi：10.1359/JBMR.090411
Reduced mechanical stress leads to bone loss, as evidenced by disuse osteoporosis in bedridden patients and astronauts. Osteocytes have been identified as major cells responsible for mechanotransduction; however, the mechanism underlying the response of bone to mechanical unloading remains poorly understood. In this study, we found that mechanical unloading of wildtype mice caused decrease of Wnt/beta-catenin signaling activity accompanied by upregulation of Sost. To further analyze the causal relationship among these events, Sost gene targeting mice were generated. We showed that sclerostin selectively inhibited Wnt/beta-catenin in vivo, and sclerostin suppressed the activity of osteoblast and viability of osteoblasts and osteocytes. Interestingly, Sost(-/-) mice were resistant to mechanical unloading-induced bone loss. Reduction in bone formation in response to unloading was also abrogated in the mutant mice. Moreover, in contrast to wildtype mice, Wnt/beta-catenin signaling was not altered by unloading in Sost(-/-) mice. Those data implied that sclerostin played an essential role in mediating bone response to mechanical unloading, likely through Wnt/beta-catenin signaling. Our findings also indicated sclerostin is a promising target for preventing disuse osteoporosis. J Bone Miner Res 2009;24:1651-1661. Published online on April 27, 2009; doi: 10.1359/JBMR.090411