Emerging evidence is revealing that microRNAs (miRNAs) play essential roles in mechanosensing for regulating osteogenesis. However, no mechanoresponsive miRNAs have been identified in human bone specimens./nMethods: Bedridden and aged patients, hindlimb unloaded and aged mice, and Random Positioning Machine and primary aged osteoblasts were adopted to simulate mechanical unloading conditions at the human, animal and cellular levels, respectively. Treadmill exercise and Flexcell cyclic mechanical stretching were used to simulate mechanical loading in vivo and in vitro, respectively./nResults: Here, we found increased miR-138-5p levels with a lower degree of bone formation in bone specimens from bedridden and aged patients. Loss- and gain-of-function studies showed that miR-138-5p directly targeted microtubule actin crosslinking factor 1 (MACF1) to inhibit osteoblast differentiation under different mechanical conditions. Regarding translational medicine, bone-targeted inhibition of miR-138-5p attenuated the decrease in the mechanical bone anabolic response in hindlimb unloaded mice. Moreover, bone-targeted inhibition of miR-138-5p sensitized the bone anabolic response to mechanical loading in both miR-138-5p transgenic mice and aged mice to promote bone formation./nConclusion: These data suggest that miR-138-5p as a mechanoresponsive miRNA accounts for the mechanosensitivity of the bone anabolic response and that inhibition of miR-138-5p in osteoblasts may be a novel bone anabolic sensitization strategy for ameliorating disuse or senile osteoporosis.

中文翻译：

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沉默miR-138-5p使骨骼合成代谢作用对机械刺激敏感

新兴证据表明，微RNA（miRNA）在调控成骨的机械传感中起着至关重要的作用。然而，尚未在人体骨标本中鉴定出具有机械响应性的miRNA。/n方法：卧床和老年患者，后肢卸载和老年小鼠，随机定位机和原代成年成骨细胞用于模拟人，动物和细胞的机械卸载条件级别。踏车运动和环状Flexcell牵张机械拉伸被用来模拟机械负载在体内和体外，respectively./n结果：在这里，我们发现卧床和老年患者的骨标本中miR-138-5p水平升高，而骨形成程度降低。功能丧失和功能增强研究表明，miR-138-5p直接针对微管肌动蛋白交联因子1（MACF1），以在不同的机械条件下抑制成骨细胞分化。关于转化医学，miR-138-5p的骨靶向抑制作用减轻了后肢空载小鼠的机械性骨合成代谢反应的降低。此外，针对miR-138-5p的骨靶向抑制使miR-138-5p转基因小鼠和成年小鼠中的骨合成代谢对机械负荷的反应均敏感，从而促进了骨形成。 这些数据表明，作为机械响应性miRNA的miR-138-5p可以解释骨合成代谢反应的机械敏感性，而在成骨细胞中抑制miR-138-5p可能是一种新型的骨合成代谢致敏性战略，可改善废弃或老年性骨质疏松症。