2. Academic Validation
  3. Itaconate attenuates osteoarthritis by inhibiting STING/NF-κB axis in chondrocytes and promoting M2 polarization in macrophages

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

  • Biochem Pharmacol. 2022 Apr;198:114935. doi: 10.1016/j.bcp.2022.114935.
Libin Ni 1,  Zhen Lin 1,  Sunli Hu 1,  Yifeng Shi 1,  Zhichen Jiang 1,  Jiayi Zhao 1,  Yifei Zhou 1,  Yaosen Wu 1,  Naifeng Tian 1,  Liaojun Sun 1,  Aimin Wu 1,  Zongyou Pan 2,  Xiaolei Zhang 3,  Xiangyang Wang 4
Affiliations

Affiliations

  • 1 Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China; Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou, Zhejiang Province, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang Province, China.
  • 2 Department of Orthopaedics, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang Province, China. Electronic address: panzongyou@zju.edu.cn.
  • 3 Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China; Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou, Zhejiang Province, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang Province, China; Chinese Orthopaedic Regenerative Medicine Society, Hangzhou, Zhejiang Province, China. Electronic address: zhangxiaolei@wmu.edu.cn.
  • 4 Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China; Key Laboratory of Orthopaedics of Zhejiang Province, Wenzhou, Zhejiang Province, China; The Second School of Medicine, Wenzhou Medical University, Wenzhou, Zhejiang Province, China. Electronic address: xiangyangwang@wmu.edu.cn.
PMID: 35104478 DOI: 10.1016/j.bcp.2022.114935
Abstract

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.

Keywords

Chondrocytes; Itaconate; Macrophages; Osteoarthritis; STING.

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