Deng Xiaofeng, Xu Haoran, Pan Chunran, Hao Xiaoxia, Liu Jiawei, Shang Xingru, Chi Ruimin, Hou Wenjie, Xu Tao
Department of Rehabilitation, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Life Sci. 2023 Nov 1;332:122020. doi: 10.1016/j.lfs.2023.122020. Epub 2023 Aug 12.
The major pathological mechanisms of osteoarthritis (OA) progression include inflammation, autophagy, and apoptosis, etc. Moderate mechanical strain and exercise effectively improve chondrocyte degeneration by reducing these adverse factors. Mitofusin 2 (MFN2) is a crucial regulatory factor associated with inflammation, autophagy and apoptosis, and its expression is regulated by exercise. This study aims to elucidate the effects of moderate mechanical strain and exercise on MFN2 expression and its influence on OA progression.
Destabilization of the medial meniscus (DMM) surgery was performed on rats to induce an OA rat model. Subsequently, adeno-associated virus (overexpression/knockdown) intra-articular injection or moderate treadmill exercise was administered to evaluate the effects of these treatments on MFN2 expression and OA progression. Overexpressed plasmids and siRNA vectors were used to regulate MFN2 expression in chondrocytes. An inflammatory degeneration cell model was generated by IL-1β stimulation. Moderate mechanical strain was applied to MFN2-overexpressing cells to explore their interactions.
MFN2 overexpression aggravated inflammation by activating the NF-κB and P38 pathways and induced excessive autophagy by inhibiting the PI3K/AKT/mTOR pathway, thereby causing chondrocyte apoptosis and metabolic disorder. Moderate mechanical strain partially reversed these adverse effects. In the DMM rat model, MFN2 overexpression in articular cartilage exacerbated OA progression, whereas MFN2 knockdown and treadmill exercise alleviated cartilage degeneration, inflammation, and mechanical pain.
MFN2 is a critical factor mediating the association between inflammation and excessive autophagy in OA progression. Moderate mechanical strain and treadmill exercise may improve OA through downregulating MFN2 expression. This study may provide a theoretical basis for exercise therapy in OA treatment.
骨关节炎（OA）进展的主要病理机制包括炎症、自噬和凋亡等。适度的机械应变和运动可通过减少这些不利因素有效改善软骨细胞退变。线粒体融合蛋白2（MFN2）是与炎症、自噬和凋亡相关的关键调节因子，其表达受运动调节。本研究旨在阐明适度机械应变和运动对MFN2表达的影响及其对OA进展的作用。
对大鼠进行内侧半月板不稳定（DMM）手术以诱导OA大鼠模型。随后，进行腺相关病毒（过表达/敲低）关节内注射或适度跑步机运动，以评估这些处理对MFN2表达和OA进展的影响。使用过表达质粒和小干扰RNA载体调节软骨细胞中MFN2的表达。通过白细胞介素-1β刺激建立炎症退变细胞模型。对过表达MFN2的细胞施加适度机械应变以探讨它们之间的相互作用。
MFN2过表达通过激活核因子-κB和P38通路加重炎症，并通过抑制磷脂酰肌醇-3激酶/蛋白激酶B/哺乳动物雷帕霉素靶蛋白通路诱导过度自噬，从而导致软骨细胞凋亡和代谢紊乱。适度机械应变部分逆转了这些不利影响。在DMM大鼠模型中，关节软骨中MFN2过表达加剧了OA进展，而MFN2敲低和跑步机运动减轻了软骨退变、炎症和机械性疼痛。
MFN2是OA进展中炎症与过度自噬关联的关键介导因子。适度机械应变和跑步机运动可能通过下调MFN2表达改善OA。本研究可为OA治疗中的运动疗法提供理论依据。
