Mechanical overloading causes mitochondrial superoxide and SOD2 imbalance in chondrocytes resulting in cartilage degeneration

• DOI: 10.1038/srep11722
• Publication Date: 2015-06-25T11:01:30Z
• Authors: Masato Koike; Hidetoshi Nojiri; Yusuke Ozawa; Kenji Watanabe; Yuta Muramatsu; Haruka Kaneko; Daichi Morikawa; Keiji Kobayashi; Yoshitomo Saita; Takahisa Sasho; Takuji Shirasawa; Koutaro Yokote; Kazuo Kaneko; Takahiko Shimizu
• Keywords: Cartilage, Articular; Mice, Knockout; Paraquat; 0301 basic medicine; Herbicides; Reverse Transcriptase Polymerase Chain Reaction; Blotting, Western; Gene Expression; Mice, Transgenic; Ascorbic Acid; Article; Antioxidants; Injections, Intra-Articular; Mitochondria; Mice, Inbred C57BL; Microscopy, Electron; 03 medical and health sciences; Chondrocytes; Animals; Humans; Stress, Mechanical; Cartilage Diseases; Cells, Cultured

AbstractMechanical stress and aging are major risk factors of cartilage degeneration. Human studies have previously reported that oxidative damage increased, while SOD2 protein was reciprocally downregulated in osteoarthritic degenerated cartilage. However, it remains unclear whether mitochondrial superoxide imbalance in chondrocytes causes cartilage degeneration. We herein demonstrate that mechanical loading promoted mitochondrial superoxide generation and selective Sod2 downregulation in chondrocytes in vivo and that mitochondrial superoxide inducer also downregulated Sod2 expression in chondrocytes in vitro. A genetically manipulated model revealed that Sod2 deficiency in chondrocytes also resulted in mitochondrial superoxide overproduction and dysfunction, thus leading to cartilage degeneration. Intra-articular injection of a permeable antioxidant effectively suppressed the mechanical loading-induced mitochondrial superoxide generation and cartilage degeneration in mice. Our findings demonstrate that mitochondrial superoxide plays a pivotal role in the development and progression of osteoarthritis and the mitochondrial superoxide balance may therefore be a promising target for the treatment of cartilage degeneration.