Acupuncture suppresses the endoplasmic reticulum stress-c-Jun N-terminal kinase pathway to inhibit chondrocyte apoptosis and attenuate knee osteoarthritis.

backgroundKnee osteoarthritis (KOA) is a degenerative joint disease characterized by progressive cartilage degradation, in which chondrocyte apoptosis plays a pivotal role. Acupuncture is widely used for KOA management, but its underlying molecular mechanisms remain poorly understood. Endoplasmic reticulum (ER) stress-induced apoptosis via the c-Jun N-terminal kinase (JNK) pathway is a critical driver of chondrocyte death in KOA. This study aimed to investigate whether acupuncture exerts its chondroprotective effects by modulating the ER stress-JNK signaling axis.

methodsA rat model of KOA was established by joint immobilization. Fifty rats were randomly assigned to five groups: Normal, Model, Model+Acupuncture (Acu), Model+ Acu+Anisomycin (JNK activator), and Model+SP600125 (JNK inhibitor). The therapeutic efficacy of a 4-week acupuncture regimen was evaluated through behavioral scores, radiographic imaging, and histological analysis. Unbiased RNA sequencing was performed to identify key signaling pathways. The mechanism was further validated through TUNEL staining, transmission electron microscopy (TEM), Western blot, RT-qPCR, immunofluorescence, and ELISA.

resultsUnbiased transcriptomic analysis identified the ER stress and MAPK/JNK signaling pathways as key targets of acupuncture. Acupuncture significantly improved joint function, alleviated cartilage degradation, and preserved proteoglycan content in KOA rats. Mechanistically, acupuncture suppressed the expression of the ER stress marker IRE1α, inhibited the phosphorylation of JNK, and consequently downregulated the pro-apoptotic Bax/Bcl-2 ratio and Caspase-3 expression. This led to a marked decrease in chondrocyte apoptosis and restoration of ER homeostasis, as confirmed by TUNEL and TEM. Crucially, the anti-apoptotic effects of acupuncture were significantly counteracted by the JNK activator Anisomycin. In addition, acupuncture remodels the systemic inflammatory network by suppressing the production of proinflammatory cytokines IL-1β and TNF-α, which triggers a compensatory upregulation of the anti-inflammatory mediator IL-10.

conclusionOur findings demonstrate for the first time that acupuncture ameliorates KOA by inhibiting chondrocyte apoptosis via suppression of the ER stress-JNK signaling pathway. This study provides a novel and robust mechanistic rationale for the clinical application of acupuncture and highlights the ER stress-JNK axis as a promising therapeutic target for KOA.