Osteoarthritis (OA) is the most common joint disease with an unsatisfactory therapy outcome and characterized by the degradation of articular cartilage and synovial inflammation. Here, we isolated bone marrow mesenchymal stem cells (BMSCs) from rat’s bone marrow and BMSC-derived exosome (BMSCs-Exo) from BMSCs successfully. MiR-135b was proved to be highly expressed in TGF-β1-stimulated BMSC-derived exosomes (BMSCs-Exo TGF-β1 ). Then, our results demonstrated that BMSCs-Exo TGF-β1 reduced OA-induced upregulation of pro-inflammatory factors in rat’s serum and damage in cartilage tissues, which was then reversed by miR-135b decreasing. Subsequently, we found that the OA-resulted M1 polarization of synovial macrophages (SMs) was repressed by BMSCs-Exo TGF-β1 , this effect of BMSCs-Exo TGF-β1 was limited by miR-135b decreasing. We also proved that M2 polarization of SMs can be induced by miR-135b mimics. Furthermore, we found that the promotory effect of miR-135b and BMSCs-Exo TGF-β1 on M2 SMs polarization was reversed by increasing of MAPK6. Overall, our data showed that BMSCs-Exo TGF-β1 attenuated cartilage damage in OA rats through carrying highly expressed miR-135b. Mechanistically, miR-135b promoted M2 polarization of SMs through targeting MAPK6, thus improving cartilage damage. Our study provided a novel regulatory mechanism of BMSCs-Exo in OA development and revealed a new potential treatment target of OA.

中文翻译：

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TGF-β1修饰的MSC衍生的外泌体miR-135b通过靶向MAPK6促进M2滑膜巨噬细胞极化减轻软骨损伤

骨关节炎（OA）是最常见的关节疾病，治疗效果不理想，其特征是关节软骨退化和滑膜炎症。在这里，我们成功地从大鼠骨髓中分离出骨髓间充质干细胞 (BMSCs)，并成功地从 BMSCs 中分离出 BMSCs 衍生的外泌体 (BMSCs-Exo)。MiR-135b 被证明在 TGF-β1 刺激的 BMSC 衍生的外泌体（BMSCs-Exo TGF-β1）中高度表达。然后，我们的结果表明，BMSCs-Exo TGF-β1 减少了 OA 诱导的大鼠血清中促炎因子的上调和软骨组织的损伤，然后通过 miR-135b 的减少逆转。随后，我们发现 OA 导致的滑膜巨噬细胞 (SMs) 的 M1 极化被 BMSCs-Exo TGF-β1 抑制，BMSCs-Exo TGF-β1 的这种作用受到 miR-135b 减少的限制。我们还证明了 miR-135b 模拟物可以诱导 SM 的 M2 极化。此外，我们发现 miR-135b 和 BMSCs-Exo TGF-β1 对 M2 SMs 极化的促进作用被 MAPK6 的增加逆转。总体而言，我们的数据显示 BMSCs-Exo TGF-β1 通过携带高表达的 miR-135b 减轻 OA 大鼠的软骨损伤。从机制上讲，miR-135b 通过靶向 MAPK6 促进 SM 的 M2 极化，从而改善软骨损伤。我们的研究提供了 BMSCs-Exo 在 OA 发展中的新调控机制，并揭示了 OA 的新潜在治疗靶点。我们的数据表明，BMSCs-Exo TGF-β1 通过携带高表达的 miR-135b 减轻 OA 大鼠的软骨损伤。从机制上讲，miR-135b 通过靶向 MAPK6 促进 SM 的 M2 极化，从而改善软骨损伤。我们的研究提供了 BMSCs-Exo 在 OA 发展中的新调控机制，并揭示了 OA 的新潜在治疗靶点。我们的数据表明，BMSCs-Exo TGF-β1 通过携带高表达的 miR-135b 减轻 OA 大鼠的软骨损伤。从机制上讲，miR-135b 通过靶向 MAPK6 促进 SM 的 M2 极化，从而改善软骨损伤。我们的研究提供了 BMSCs-Exo 在 OA 发展中的新调控机制，并揭示了 OA 的新潜在治疗靶点。