Icariin Alleviates IL-1β-Induced Matrix Degradation By Activating The Nrf2/ARE Pathway In Human Chondrocytes

Shi Zuo,1,* Wei Zou,2,3,* Rong-Min Wu,4 Jing Yang,5 Jian-Nan Fan,2 Xue-Ke Zhao,5 Hai-Yang Li1 1Department of Hepatobiliary Surgery, The Hospital Affiliated to Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China; 2Department of Sports Medicine, The Hospital Affiliated to Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China; 3Department of Orthopedics, The Fourth People’s Hospital of Guiyang, Guizhou, People’s Republic of China; 4Department of Ultrasonography, The Maternity Hospital of Guizhou, Guiyang, Guizhou, People’s Republic of China; 5Department of Infectious Disease, The Hospital Affiliated to Guizhou Medical University, Guiyang, Guizhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hai-Yang LiDepartment of Hepatobiliary Surgery, The Hospital Affiliated to Guizhou Medical University, No.28, Guiyi Street, Guiyang, Guizhou 550004, People’s Republic of ChinaEmail haiyangli666@sohu.comJian-Nan FanDepartment of Sports Medicine, The Hospital Affiliated to Guizhou Medical University, No.28, Guiyi Street, Guiyang, Guizhou 550004, People’s Republic of ChinaEmail publetscientific@126.comObjective: Osteoarthritis (OA) is characterized by progressive matrix destruction of articular cartilage. This study aimed to investigate the potential antioxidative and chondroprotective effects and underlying mechanism of Icariin (ICA) in interleukin-1 beta (IL-1β)-induced extracellular matrix (ECM) degradation of OA cartilage.Methods: Human chondrocyte cell line HC-A was treated with different doses of ICA, and then MTT assay and PI staining were used to estimate ICA-induced chondrocyte apoptosis. Intracellular ROS and superoxide dismutase (SOD) and glutathione peroxidase (GPX) were measured after treatment by IL-1β with or without ICA. The mRNA and protein expression levels of redox transcription factor Nrf2 and the downstream effector SOD-1, SOD-2, NQO-1 and HO-1 were assayed to explore the detailed mechanism by which ICA alleviates ECM degradation. Finally, to expound the role of Nrf2 in ICA-mediated chondroprotection, we specifically depleted Nrf2 in human chondrocytes and then pretreated them with ICA followed by IL-1β.Results: ICA had no cytotoxic effects on human chondrocytes and 10−9 M was selected as the optimum concentration. ROS induced by IL-1β could drastically activate matrix-degrading proteases and ICA could significantly rescue the matrix degradation and excess ROS generation caused by IL-1β. We observed that ICA activated the Nrf2/ARE pathway, consequently upregulating the generation of GPX and SOD. Ablation of Nrf2 abrogated the chondroprotective and antioxidative effects of ICA in IL-1β-treated chondrocytes.Conclusion: ICA alleviates IL-1β-induced matrix degradation and eliminates ROS by activating the Nrf2/ARE pathway.Keywords: icariin, Nrf2 signaling, ROS, human chondrocyte, ECM degradation