ROS-induced imbalance of the miR-34a-5p/SIRT1/p53 axis triggers chronic chondrocyte injury and inflammation
Meng Zhou,
Bi Liu,
Hai-Ming Ye,
Jia-Ning Hou,
Yi-Cong Huang,
Peng Zhang,
Liang Gao,
Hao-Tian Qin,
Yi-Fei Yang,
Hui Zeng,
Bin Kang,
Fei Yu,
De-Li Wang,
Ming Lei
Affiliations
Meng Zhou
Department of Bone and Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, Guangdong, China; National and Local Joint Engineering Research Center for Orthopedic Biomaterials, Shenzhen, 518036, Guangdong, China; Shenzhen Key Laboratory of Orthopaedic Diseases and Biomaterials Research, Shenzhen, 518036, Guangdong, China; Department of Orthopedics and Traumatology, The Chinese University of Hong Kong, Hong Kong SAR, 999077, China; Institute for Tissue Engineering and Regenerative Medicine, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, 999077, China
Bi Liu
Department of Orthopedics, Shenzhen People's Hospital, Shenzhen, 518020, Guangdong, China; The Second Clinical Medical College, Jinan University, Shenzhen, 518020, Guangdong, China; The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, 518020, Guangdong, China
Hai-Ming Ye
Department of Bone and Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, Guangdong, China; National and Local Joint Engineering Research Center for Orthopedic Biomaterials, Shenzhen, 518036, Guangdong, China; Shenzhen Key Laboratory of Orthopaedic Diseases and Biomaterials Research, Shenzhen, 518036, Guangdong, China
Jia-Ning Hou
Department of General Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, Guangdong, China
Yi-Cong Huang
Department of Orthopedic Surgery, Affiliated Dongguan People's Hospital, Southern Medical University, Dongguan, 523000, China
Peng Zhang
Department of Bone and Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, Guangdong, China; National and Local Joint Engineering Research Center for Orthopedic Biomaterials, Shenzhen, 518036, Guangdong, China; Shenzhen Key Laboratory of Orthopaedic Diseases and Biomaterials Research, Shenzhen, 518036, Guangdong, China
Liang Gao
Center for Clinical Medicine, Huatuo Institute of Medical Innovation (HTIMI), Berlin, Germany
Hao-Tian Qin
Department of Bone and Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, Guangdong, China; National and Local Joint Engineering Research Center for Orthopedic Biomaterials, Shenzhen, 518036, Guangdong, China; Shenzhen Key Laboratory of Orthopaedic Diseases and Biomaterials Research, Shenzhen, 518036, Guangdong, China
Yi-Fei Yang
Department of Bone and Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, Guangdong, China; National and Local Joint Engineering Research Center for Orthopedic Biomaterials, Shenzhen, 518036, Guangdong, China; Shenzhen Key Laboratory of Orthopaedic Diseases and Biomaterials Research, Shenzhen, 518036, Guangdong, China
Hui Zeng
Department of Bone and Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, Guangdong, China; National and Local Joint Engineering Research Center for Orthopedic Biomaterials, Shenzhen, 518036, Guangdong, China; Shenzhen Key Laboratory of Orthopaedic Diseases and Biomaterials Research, Shenzhen, 518036, Guangdong, China
Bin Kang
Department of Bone and Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, Guangdong, China; National and Local Joint Engineering Research Center for Orthopedic Biomaterials, Shenzhen, 518036, Guangdong, China; Shenzhen Key Laboratory of Orthopaedic Diseases and Biomaterials Research, Shenzhen, 518036, Guangdong, China
Fei Yu
Department of Bone and Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, Guangdong, China; National and Local Joint Engineering Research Center for Orthopedic Biomaterials, Shenzhen, 518036, Guangdong, China; Shenzhen Key Laboratory of Orthopaedic Diseases and Biomaterials Research, Shenzhen, 518036, Guangdong, China; Corresponding author. Department of Bone and Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, Guangdong, China.
De-Li Wang
Department of Bone and Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, Guangdong, China; National and Local Joint Engineering Research Center for Orthopedic Biomaterials, Shenzhen, 518036, Guangdong, China; Shenzhen Key Laboratory of Orthopaedic Diseases and Biomaterials Research, Shenzhen, 518036, Guangdong, China; Corresponding author. Department of Bone and Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, Guangdong, China.
Ming Lei
Department of Bone and Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, Guangdong, China; National and Local Joint Engineering Research Center for Orthopedic Biomaterials, Shenzhen, 518036, Guangdong, China; Shenzhen Key Laboratory of Orthopaedic Diseases and Biomaterials Research, Shenzhen, 518036, Guangdong, China; Corresponding author. Department of Bone and Joint Surgery, Peking University Shenzhen Hospital, Shenzhen, 518036, Guangdong, China.
Osteoarthritis is a chronic degenerative disease based on the degeneration and loss of articular cartilage. Inflammation and aging play an important role in the destruction of the extracellular matrix, in which microRNA (miRNA) is a key point, such as miRNA-34a-5p. Upregulation of miRNA-34a-5p was previously reported in a rat OA model, and its inhibition significantly suppressed interleukin (IL)-1β-induced apoptosis in rat chondrocytes. However, Oxidative stress caused by reactive oxygen species (ROS) can exacerbate the progression of miRNA regulated OA by mediating inflammatory processes. Thus, oxidative stress effects induced via tert-butyl hydroperoxide (tBHP) in human chondrocytes were assessed in the current research by evaluating mitochondrial ROS production, mitochondrial cyclooxygenase (COX) activity, and cell apoptosis. We also analyzed the activities of antioxidant enzymes including glutathione peroxidase (GSH-Px), catalase (CAT), and superoxide dismutase (SOD). Additionally, inflammatory factors, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-8, and IL-24, which contribute to OA development, were detected by enzyme-linked immunosorbent assay (ELISA). The results of this study indicated that miR-34a-5p/silent information regulator 1 (SIRT1)/p53 axis was involved in the ROS-induced injury of human chondrocytes. Moreover, dual-luciferase assay revealed that SIRT1 expression was directly regulated by miR-34a-5p, indicating the presence of a positive feedback loop in the miR-34a-5p/SIRT1/p53 axis that plays an important role in cell survival. However, ROS disrupted the miR-34a-5p/SIRT1/p53 axis, leading to the development of OA, and articular injection of SIRT1 agonist, SRT1720, in a rat model of OA effectively ameliorated OA progression in a dose-dependent manner. Our study confirms that miRNA-34a-5p could participate in oxidative stress responses caused by ROS and further regulate the inflammatory process via the SIRT1/p53 signaling axis, ultimately affecting the onset of OA, thus providing a new treatment strategy for clinical treatment of OA.
