Alleviating osteoarthritis-induced damage through extracellular vesicles derived from inflammatory chondrocytes

The role of extracellular vesicles (EVs) derived from inflammatory chondrocytes in EV-based therapy for osteoarthritis (OA) has received little attention. We examined the effects of EVs derived from both normal rat chondrocytes (nEVs) and IL-1β-treated rat chondrocytes (iEVs) on IL-1β-treated rat chondrocytes, macrophages, and osteoblasts, alongside mRNA-seq and miRNA-seq analyses of both them. Additionally, nEVs and iEVs were administered intra-articularly in the joints of rat models subjected to anterior cruciate ligament transection (ACLT), and the morphological alterations across the joints were assessed. These findings indicated that iEVs, compared with nEVs, significantly enhanced collagen II synthesis in IL-1β-treated chondrocytes, accompanied by marked increases in ER stress and autophagy. In comparison to nEVs, iEVs exhibited a greater effect on facilitating M2-type macrophage polarization while simultaneously diminishing M1-type polarization, a process likely mediated by the downregulation of chemotactic cytokines such as Cxcl10, Ccl5, Cxcl9, Cxcl1, and Cxcl11. iEVs exerted a more pronounced influence on the phenotypic characteristics of IL-1β-treated osteoblasts than nEVs. In the ACLT-rat model, iEVs, akin to nEVs, effectively mitigated articular cartilage degradation. However, there was no significant difference in OARSI Scores between the two groups, despite iEVs exerting a greater effect on increasing hyaline cartilage thickness and proteoglycan content. iEVs were superior to nEVs in attenuating synovium inflammation and promoting trabecula formation in the femur subchondral bone. Consequently, iEVs, akin to nEVs, significantly alleviated OA-induced damage. Moreover, iEVs outperformed nEVs in certain aspects, notably in augmenting hyaline cartilage, reducing synovium inflammation, and promoting trabecular formation in the subchondral bone during the early stage of OA.