Department of Orthopaedics, First Hospital of China Medical University, No. 155, Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, People's Republic of China.
Department of Orthopaedics, Dashiqiao Central Hospital, Shenyang, 115100, People's Republic of China.
Cell Tissue Res. 2020 Jul;381(1):99-114. doi: 10.1007/s00441-020-03193-x. Epub 2020 May 6.
Mesenchymal stem cells (MSCs) have been demonstrated to serve as targets for the treatment of osteoarthritis (OA) and exosomes derived from MSCs also display chondroprotective effects. This study aims to investigate the regulatory role of exosomal microRNA-9-5p (miR-9-5p) secreted by bone marrow-derived MSCs (BM-MSCs) on OA in a rat model induced by anterior cruciate ligament/medial collateral ligament transection. Luciferase reporter assay was conducted to verify the putative miR-9-5p binding sites to 3'UTR of syndecan-1 (SDC1). Additionally, an intra-articular injection of miR-9-5p carried by BM-MSC-derived exosomes or liposomes into rats with OA-like damage was performed to ascertain the role of exosomal miR-9-5p and a gain-of-function study of SDC1 was carried out to explore the potential mechanism in relation to SDC1. Subsequently, the expression of SDC1 was determined and the levels of inflammatory factors (IL-1, IL-6, TNF-α and CRP) and oxidative stress injury indicators (NO, MDA, iNOS, COX2 and SOD), the contents of AKP as well as the levels of OA-related factors (MMP-13, COMP and OCN) were measured. Injection of miR-9-5p-contained exosomes resulted in an alleviation of inflammation and OA-like damage, which was evidenced by downregulated levels of inflammatory factors, reduced oxidative stress injury and decreased OCN, MMP-13, COMP and AKP levels. As a target gene of miR-9-5p, the upregulation of SDC1 led to aggravation of inflammation and OA-like damage, which is opposite to exosomal miR-9-5p. To conclude, these findings suggest the anti-inflammatory and chondroprotective effects of BM-MSC-derived exosomal miR-9-5p on OA via regulation of SDC1.
间充质干细胞 (MSCs) 已被证明可作为治疗骨关节炎 (OA) 的靶点，并且 MSC 来源的外泌体也显示出软骨保护作用。本研究旨在探讨骨髓间充质干细胞 (BM-MSCs) 分泌的外泌体 microRNA-9-5p (miR-9-5p) 在 ACL/MC 切断诱导的大鼠 OA 模型中的调节作用。通过荧光素酶报告实验验证 miR-9-5p 与 syndecan-1 (SDC1) 3'UTR 之间的假定结合位点。此外，通过向具有 OA 样损伤的大鼠关节内注射载有 miR-9-5p 的 BM-MSC 衍生的外泌体或脂质体，确定外泌体 miR-9-5p 的作用，并进行 SDC1 的功能获得研究，以探讨与 SDC1 相关的潜在机制。随后，测定 SDC1 的表达水平以及炎症因子 (IL-1、IL-6、TNF-α 和 CRP) 和氧化应激损伤指标 (NO、MDA、iNOS、COX2 和 SOD)、AKP 含量以及 OA 相关因子 (MMP-13、COMP 和 OCN) 的水平。注射 miR-9-5p 载外泌体可减轻炎症和 OA 样损伤，这表现在炎症因子水平降低、氧化应激损伤减轻以及 OCN、MMP-13、COMP 和 AKP 水平降低。作为 miR-9-5p 的靶基因，SDC1 的上调导致炎症和 OA 样损伤加剧，这与外泌体 miR-9-5p 相反。总之，这些发现表明 BM-MSC 衍生的外泌体 miR-9-5p 通过调节 SDC1 对 OA 具有抗炎和软骨保护作用。
