■关节软骨(AC)和滑膜的病理变化是骨关节炎(OA)的主要表现,并且与疼痛和功能限制密切相关。外泌体来源的微小RNA(miRNA)是细胞间通讯的关键调控因子,可通过参与软骨细胞的降解和滑膜巨噬细胞极化的表型转化来影响OA的进展。然而,外泌体miRNAs在软骨和滑膜OA病理进展中的具体关系和作用途径尚不清楚.
■这项研究评估了成纤维细胞样滑膜细胞(FLS)衍生的外泌体(FLS-Exos)的作用,受miR-146a的影响,对AC降解和滑膜巨噬细胞极化的影响。我们研究了体内和体外miR-146a和TRAF6之间的靶向关系,随着NF-κB信号通路的参与。
■OA大鼠滑膜外泌体中miR-146a的表达明显高于健康大鼠。体外,miR-146a的上调减少了软骨细胞凋亡,而它的下调却产生了相反的效果。在体内,来自过表达miR-146a的FLS(miR-146a-FLS-Exos)的外泌体减少了OA中的AC损伤和软骨细胞凋亡。此外,滑膜增生减少,滑膜巨噬细胞的极化从M1转移到M2。机械上,靶向miR-146a抑制TRAF6的表达,从而在先天免疫应答中调节Toll样受体4/TRAF6/NF-κB途径。
■这些发现表明miR-146a,通过FLS-Exos介导,可以通过调节软骨降解和巨噬细胞极化来缓解OA的进展,NF-κB途径参与先天免疫反应。这些见解突出了miR-146a作为OA保护剂的治疗潜力,强调外泌体miRNAs在疾病的发病机制和潜在治疗中的重要性。
UNASSIGNED: Pathological changes in the articular cartilage (AC) and synovium are major manifestations of osteoarthritis (OA) and are strongly associated with pain and functional limitations. Exosome-derived microRNAs (miRNAs) are crucial regulatory factors in intercellular communication and can influence the progression of OA by participating in the degradation of chondrocytes and the phenotypic transformation in the polarization of synovial macrophages. However, the specific relationships and pathways of action of exosomal miRNAs in the pathological progression of OA in both cartilage and synovium remain unclear.
UNASSIGNED: This study evaluates the effects of fibroblast-like synoviocyte (FLS)-derived exosomes (FLS-Exos), influenced by miR-146a, on AC degradation and synovial macrophage polarization. We investigated the targeted relationship between miR-146a and TRAF6, both in vivo and in vitro, along with the involvement of the NF-κB signaling pathway.
UNASSIGNED: The expression of miR-146a in the synovial exosomes of OA rats was significantly higher than in healthy rats. In vitro, the upregulation of miR-146a reduced chondrocyte apoptosis, whereas its downregulation had the opposite effect. In vivo, exosomes derived from miR-146a-overexpressing FLSs (miR-146a-FLS-Exos) reduced AC injury and chondrocyte apoptosis in OA. Furthermore, synovial proliferation was reduced, and the polarization of synovial macrophages shifted from M1 to M2. Mechanistically, the expression of TRAF6 was inhibited by targeting miR-146a, thereby modulating the Toll-like receptor 4/TRAF6/NF-κB pathway in the innate immune response.
UNASSIGNED: These findings suggest that miR-146a, mediated through FLS-Exos, may alleviate OA progression by modulating cartilage degradation and macrophage polarization, implicating the NF-κB pathway in the innate immune response. These insights highlight the therapeutic potential of miR-146a as a protective agent in OA, underscoring the importance of exosomal miRNAs in the pathogenesis and potential treatment of the disease.