Exosomal microRNA-363 mediates the destructive effect of M1 macrophages on chondrocytes by repressing G3BP2

M1 polarization of synovial macrophages contributes to cartilage degeneration and osteoarthritis (OA) development. However, limited knowledge is available about how M1 macrophages affect the biological properties of chondrocytes. This study aimed to explore the role of exosomal microRNAs (miRs) released from M1 macrophages in modulating the proliferation and survival of chondrocytes. Through bioinformatic analysis and experimental validation, we indicated that miR-363 was selectively induced in M1 macrophages (CD68⁺CD80⁺) but not M2 macrophages (CD68⁺CD206⁺). The upregulation of miR-363 in M1 macrophages depended on the activation of STAT1 signaling. Clinically, OA patients had a significantly higher miR-363 level in synovial fluid than control individuals without OA. Functional studies revealed that inhibition of miR-363 blocked the M1 macrophage polarization induced by lipopolysaccharide and IFN-γ. Moreover, exosomal miR-363 released from M1 macrophages significantly suppressed the proliferation and survival and induced inflammatory gene expression in chondrocytes. G3BP2 was identified as a target gene for miR-363 and could be negatively regulated by miR-363. Knockdown of G3BP2 recapitulated the effect of miR-363 overexpression on chondrocytes. Most importantly, enforced expression of G3BP2 attenuated miR-363-induced apoptosis and inflammatory response in chondrocytes. In conclusion, miR-363 plays an indispensable role in M1 macrophage polarization and can be released from M1 macrophages via exosomes to cause chondrocyte injury and inflammation. The miR-363/G3BP2 axis may represent a promising target for the prevention of OA development.