Itaconate attenuates osteoarthritis by inhibiting STING/NF-κB axis in chondrocytes and promoting M2 polarization in macrophages

• Published in: Biochemical pharmacology Vol. 198; p. 114935
• Main Authors: Ni, Libin, Lin, Zhen, Hu, Sunli, Shi, Yifeng, Jiang, Zhichen, Zhao, Jiayi, Zhou, Yifei, Wu, Yaosen, Tian, Naifeng, Sun, Liaojun, Wu, Aimin, Pan, Zongyou, Zhang, Xiaolei, Wang, Xiangyang
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 01.04.2022
• Subjects: Animals; Cartilage, Articular - metabolism; Chondrocytes; Disease Models, Animal; Inflammation - metabolism; Interleukin-1beta - metabolism; Itaconate; Macrophages; Macrophages - metabolism; Mice; NF-E2-Related Factor 2 - metabolism; NF-kappa B - metabolism; Osteoarthritis; Osteoarthritis - pathology; STING; Succinates; Itaconate; DMSO; HO-1; 4-OI; Macrophages; LPS; NF-κB; OA; Arg-1; Nrf2; cGAS; Irg-1; COX2; CCK-8; PBS; NQO1; DMM; HE staining; qRT-PCR; DAPI; CM; Chondrocytes; EdU; STING; Ym1; Osteoarthritis; ELISA
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2022.114935

[Display omitted] Osteoarthritis (OA) is a progressive joint disease characterized by the degradation and destruction of articular cartilage, which is involved with pathological microenvironmental alterations induced by damaged chondrocytes and inflammatory macrophages. However, the current therapies cannot effectively alleviate the progression of OA. Our previous studies have shown that the pathological process of OA progression is accompanied by DNA damage, and inhibition of STING, a key molecule in DNA damage, may become a potential method for the treatment of OA. Itaconate, a metabolite highly expressed in macrophages under inflammatory conditions, has shown a wide range of anti-inflammatory effects, but its effect on OA and its underlying mechanism has not yet been studied. In this study, we found that exogenous supplementation of itaconate can activate Nrf2, and accordingly inhibit the STING-dependent NF-κB pathway, thereby alleviating the inflammation, ECM degeneration and senescence of chondrocytes stimulated by IL-1β. In addition, itaconate can regulate the polarization of RAW264.7 macrophages, further reducing the apoptosis of chondrocytes. In vivo, intra-articular injection of itaconate reduces the degradation of cartilage and inflammation of synovial membrane in the mouse OA model. In conclusion, the present work suggests that exogenous supplementation of itaconate inhibits the inflammation, senescence and ECM degeneration of chondrocytes through the Nrf2/STING/NF-κB axis and regulates the polarization of synovial macrophages, thereby ameliorating the progression of OA, which supports that itaconate as a potential drug for the treatment of OA.