Sost, independent of the non-coding enhancer ECR5, is required for bone mechanoadaptation.
Sost, independent of the non-coding enhancer ECR5, is required for bone mechanoadaptation.
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DOI：
10.1016/j.bone.2016.09.001
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发表时间：
2016-11
期刊：
影响因子：
4.1
通讯作者：
Genetos DC
中科院分区：
文献类型：
--
作者：
Robling AG;Kang KS;Bullock WA;Foster WH;Murugesh D;Loots GG;Genetos DC
硬化蛋白（Sost）是骨形成的负调节因子，作用于Wnt信号通路。Sost在mRNA和蛋白质水平上受到机械调节，因此在骨细胞和循环中，加载抑制和卸载增强Sost的表达。非编码进化保守的增强子ECR5先前已被报道为骨细胞中Sost表达调节所需的转录调控元件。在这里，我们探索了ECR5或其他几种可能的转录增强子在机械刺激下调节Sost表达的机制。我们发现，野生型和Sost - / -小鼠体内的尺骨负荷同样具有骨合成代谢作用，尽管Sost是负载诱导的骨形成在高应变区域的适当分布所必需的。利用携带ECR5非编码增强子和异源或同源hSOST启动子的荧光素酶报告子，我们发现ECR5在体外具有机械敏感性，并且在暴露于振荡流体的成骨细胞中，ECR5驱动的荧光素酶活性降低。然而，与野生型小鼠相比，ECR5−/−小鼠在高应变区表现出相似的负载诱导骨形成程度和骨形成的骨膜分布。此外，我们发现，与Sost - / -小鼠相比，ECR5 - / -小鼠对废弃诱导的骨质流失具有抗性，而ECR5 - / -小鼠在卸载后的骨质流失程度与野生型对照小鼠相似。ECR5缺失并没有消除卸载对Sost的积极作用，这表明额外的转录调控因子和调控元件参与了负载诱导的Sost调控。
Sclerostin (Sost) is a negative regulator of bone formation that acts upon the Wnt signaling pathway. Sost is mechanically regulated at both mRNA and protein level such that loading represses and unloading enhances Sost expression, in osteocytes and in circulation. The non-coding evolutionarily conserved enhancer ECR5 has been previously reported as a transcriptional regulatory element required for modulating Sost expression in osteocytes. Here we explored the mechanisms by which ECR5, or several other putative transcriptional enhancers regulate Sost expression, in response to mechanical stimulation. We found that in vivo ulna loading is equally osteoanabolic in wildtype and Sost−/− mice, although Sost is required for proper distribution of load-induced bone formation to regions of high strain. Using Luciferase reporters carrying the ECR5 non-coding enhancer and heterologous or homologous hSOST promoters, we found that ECR5 is mechanosensitive in vitro and that ECR5-driven Luciferase activity decreases in osteoblasts exposed to oscillatory fluid flow. Yet, ECR5−/− mice showed similar magnitude of load-induced bone formation and similar periosteal distribution of bone formation to high-strain regions compared to wildtype mice. Further, we found that in contrast to Sost−/− mice, which are resistant to disuse-induced bone loss, ECR5−/− mice lose bone upon unloading to a degree similar to wildtype control mice. ECR5 deletion did not abrogate positive effects of unloading on Sost, suggesting that additional transcriptional regulators and regulatory elements contribute to load-induced regulation of Sost.
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