Emerging evidence indicates that many microRNAs (miRNAs) are indispensable regulators of osteoblast differentiation and bone formation. However, the role of miRNAs in mechanotransduction of osteoblasts remains to be elucidated. This study aimed to identify a mechanosensitive miRNA that regulates Activin A receptor type I (ACVR1)-induced osteogenic differentiation. After 4 weeks of hindlimb unloading (HLU) suspension of 6-month-old male C57BL/6J mice, femurs and tibias were harvested to extract total bone RNAs. Elevated levels of miR-208a-3p correlated with a lower degree of bone formation in whole-bone samples of HLU mice. However, in vitro overexpression of miR-208a-3p inhibited osteoblast differentiation, whereas silencing of miR-208a-3p by antagomiR-208a-3p promoted expression of osteoblast activity, bone formation marker genes, and matrix mineralization under mechanical unloading condition. Bioinformatics analysis and a luciferase assay revealed that ACVR1 is a target gene of miR-208a-3p that negatively regulates osteoblast differentiation under mechanical unloading environment. Further, this study also demonstrates that in vivo pre-treatment with antagomiR-208a-3p led to an increase in bone formation and trabecular microarchitecture and partly rescued the bone loss caused by mechanical unloading. Collectively, these results suggest that in vivo, inhibition of miRNA-208a-3p by antagomiR-208a-3p may be a potential therapeutic strategy for ameliorating bone loss.

新兴证据表明，许多microRNA（miRNA）是成骨细胞分化和骨形成必不可少的调节剂。然而，miRNA在成骨细胞机械转导中的作用尚待阐明。这项研究旨在确定一种机械敏感的miRNA，它调节I型激活素A受体（ACVR1）诱导的成骨分化。在6个月大的雄性C57BL / 6J小鼠的后肢卸载（HLU）悬浮液4周后，收获股骨和胫骨以提取总骨RNA。在HLU小鼠的全骨样本中，miR-208a-3p的水平升高与骨形成程度降低相关。但是，在体外miR-208a-3p的过表达抑制成骨细胞的分化，而antagomiR-208a-3p使miR-208a-3p沉默可促进成骨细胞活性，骨形成标记基因和基质矿化的表达。生物信息学分析和萤光素酶分析表明，ACVR1是miR-208a-3p的靶基因，在机械卸载环境下负调节成骨细胞的分化。此外，这项研究还表明，用antagomiR-208a-3p进行的体内预处理可导致骨骼形成和小梁微结构的增加，并部分挽救了机械卸载引起的骨骼损失。总的来说，这些结果表明体内，通过antagomiR-208a-3p抑制miRNA-208a-3p可能是减轻骨质流失的潜在治疗策略。