Objective: The aim of this work was to determine the effect of miR-375 on chondrocyte metabolism and oxidative stress in osteoarthritis (OA) mouse models through the JAK2/STAT3 signaling pathway. Methods: Chondrocytes were divided into control, IL-1β, IL-1β + miR-375 mimic, IL-1β + miR-375 inhibitor, IL-1β + miR-NC (negative control), and IL-1β + miR-375 inhibitor + siJAK2 groups. The chondrocyte proliferation was determined by MTT assay, the superoxide dismutase (SOD) and malondialdehyde (MDA) levels by corresponding kits, and the chondrocyte apoptosis by TUNEL staining. Furthermore, OA mouse models were divided into Sham, OA + miR-NC, and OA + miRNA-375 antagomir groups. The pathological changes were observed, and the expressions of miR-375 and the JAK2/STAT3 pathway were determined by qRT-PCR and Western blotting, respectively. Results: IL-1β-induced chondrocytes had significant increases in miR-375 and MDA, with decreased proliferation and SOD levels, as compared to the control group. Meanwhile, they also exhibited elevated apoptosis, with upregulations of ADAMTS-5 and MMP-13 and downregulations of COL2A1 and ACAN, as well as decreased p-JAK2/JAK2, p-STAT3/STAT3, and Bcl-2/Bax. However, these changes were significantly improved after transfection with miR-375 inhibitor, but transfection with miR-375 mimic resulted in severer exacerbation. Notably, the improvement of miR-375 inhibitor could be abolished by transfection with siJAK2. Furthermore, miR-375 antagomir significantly alleviated OA progression in OA mice in vivo. Conclusion: MiR-375 suppression enhanced the ability of chondrocyte to antagonize the oxidative stress and maintained the homeostasis of extracellular matrix metabolism to protect chondrocytes from OA via activation of the JAK2/STAT3 pathway, indicating that miR-375 is a potential molecular target for OA treatment.

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