Therapeutic effect and potential mechanisms of intra-articular injections of miR-140-5p on early-stage osteoarthritis in rats
Therapeutic effect and potential mechanisms of intra-articular injections of miR-140-5p on early-stage osteoarthritis in rats
复制标题
关节内注射miR-140-5p对大鼠早期骨关节炎的治疗作用及潜在机制
DOI：
10.1016/j.intimp.2021.107786
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发表时间：
2021-05-28
影响因子：
5.6
通讯作者：
Shen, Bin
中科院分区：
文献类型：
--
作者：
Cao, Fei;Chen, Yang;Shen, Bin
近年来，MicroRNAs （miRs）在骨关节炎（OA）发病机制中受到广泛关注，我们之前的研究证实，关节内注射（IAJ） miR-140-5p可缓解大鼠早期OA （EOA）的进展。本研究旨在探讨miR-140-5p单次IAJ （SIAJ）对不同分期OA和miR-140-5p多次IAJ （MIAJ）对OA的治疗效果及潜在机制。首先，手术诱导大鼠OA模型，术后1周用Cy5-miR-140-5p IAJ处理9只，分析不同时间的荧光分布。然后，对72只大鼠进行不同阶段的miR-1405p SIAJ或术后1周的miR-140-5p MIAJ治疗，并在不同时间进行宏观和组织学评估OA进展。最后，通过生物信息学预测miR-140-5p的下游靶点和潜在的分子机制，并进行部分验证。因此，关节内注射的miR-140-5p进入软骨，并能迅速被软骨细胞占用。miR-140-5p的IAJ(s)可不同程度地改善行为评分、软骨细胞数量、软骨厚度和病理评分。其中，越早给予miR-140-5p SIAJ治疗效果越好；同时，miR-140-5p的MIAJ对EOA的治疗效果优于SIAJ。预测了84个rno-miR-140-5p的潜在靶基因及其作用机制，并通过实验验证了miR-140-5p对潜在靶基因VEGFA和JAG1的影响。总的来说，miR-140-5p的IAJs通过调节大鼠的多种生物过程和途径，有效地缓解了EOA的进展，代表了一种有希望的EOA治疗方法。
MicroRNAs (miRs) receive extensive attention in osteoarthritis (OA) pathogenesis in recent years, and our previous study confirmed that an intra-articular injection (IAJ) of miR-140-5p alleviates early-stage OA (EOA) progression in rats. This study aims to investigate the therapeutic effect and potential mechanisms of single IAJ (SIAJ) of miR-140-5p on different stage OA and multiple IAJs (MIAJ) of miR-140-5p on EOA. Firstly, the OA model was surgically induced in rats, nine were treated with IAJ of Cy5-miR-140-5p at one week after surgery, and fluorescence distribution was analyzed at different times. Then, 72 rats were treated with SIAJ of miR-1405p at different stages or MIAJ of miR-140-5p at one week after surgery, and OA progression was evaluated macroscopically and histologically at different times. Finally, the downstream targets and underlying molecular mechanisms of miR-140-5p were predicted by bioinformatics and partially validated. As a result, the intraarticularly injected miR-140-5p entered cartilage and could be taken up by chondrocytes rapidly. IAJ(s) of miR-140-5p improved the behavioral scores, chondrocyte number, cartilage thickness, and pathological scores to varying degrees. Specifically, the earlier a SIAJ of miR-140-5p was administrated, the better the therapeutic effect; meanwhile, MIAJ of miR-140-5p exhibited a better therapeutic effect than SIAJ on EOA. Eighty-four potential target genes and mechanisms of rno-miR-140-5p were predicted, and the effect of miR-140-5p on the potential target genes VEGFA and JAG1 was experimentally validated. Collectively, IAJs of miR-140-5p effectively alleviate EOA progression by modulating multiple biological processes and pathways in rats, representing a promising therapeutic for EOA.