BACKGROUND Osteoblast differentiation is a vital process for fracture healing, and exosomes are nanosized membrane vesicles that can deliver therapeutic drugs easily and safely. Macrophages participate in the regulation of various biological processes in vivo, and macrophage-derived exosomes (MD-Exos) have recently been a topic of increasing research interest. However, few study has explored the link between MD-Exos and osteoblast differentiation. Herein, we sought to identify miRNAs differentially expressed between M1 and M2 macrophage-derived exosomes, and to evaluate their roles in the context of osteoblast differentiation. RESULTS We found that microRNA-5106 (miR-5106) was significantly overexpressed in M2 macrophage-derived exosomes (M2D-Exos), while its expression was decreased in M1 macrophage-derived exosomes (M1D-Exos), and we found that this exosomal miRNA can induce bone mesenchymal stem cell (BMSC) osteogenic differentiation via directly targeting the Salt-inducible kinase 2 and 3 (SIK2 and SIK3) genes. In addition, the local injection of both a miR-5106 agonist or M2D-Exos to fracture sites was sufficient to accelerate healing in vivo. CONCLUSIONS Our study demonstrates that miR-5106 is highly enriched in M2D-Exos, and that it can be transferred to BMSCs wherein it targets SIK2 and SIK3 genes to promote osteoblast differentiation.

中文翻译：

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M2巨噬细胞衍生的外泌体miRNA-5106通过靶向盐诱导性激酶2和3诱导骨间充质干细胞趋向成骨细胞命运。

背景技术成骨细胞的分化是骨折愈合的重要过程，并且外泌体是可以容易且安全地递送治疗药物的纳米级膜囊泡。巨噬细胞参与体内各种生物过程的调节，并且巨噬细胞衍生的外来体（MD-Exos）近来已成为越来越多的研究兴趣的话题。但是，很少有研究探索MD-Exos与成骨细胞分化之间的联系。在本文中，我们试图鉴定在M1和M2巨噬细胞衍生的外泌体之间差异表达的miRNA，并评估它们在成骨细胞分化中的作用。结果我们发现microRNA-5106（miR-5106）在M2巨噬细胞来源的外泌体（M2D-Exos）中明显过表达，而其表达在M1巨噬细胞来源的外泌体（M1D-Exos）中降低，并且我们发现这种外泌体miRNA可通过直接靶向盐诱导型激酶2和3（SIK2和SIK3）基因来诱导骨间充质干细胞（BMSC）成骨分化。另外，向骨折部位局部注射miR-5106激动剂或M2D-Exos足以促进体内愈合。结论我们的研究表明，miR-5106在M2D-Exos中高度富集，并且可以转移到BMSCs中，靶向SIK2和SIK3基因以促进成骨细胞分化。