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

• Published in: Scientific reports Vol. 5; no. 1; p. 11722
• Main Authors: Koike, Masato, Nojiri, Hidetoshi, Ozawa, Yusuke, Watanabe, Kenji, Muramatsu, Yuta, Kaneko, Haruka, Morikawa, Daichi, Kobayashi, Keiji, Saita, Yoshitomo, Sasho, Takahisa, Shirasawa, Takuji, Yokote, Koutaro, Kaneko, Kazuo, Shimizu, Takahiko
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25-06-2015; Nature Publishing Group
• Subjects: 45/41; 631/443/7; 64; 64/110; 64/60; 692/699/1670/407; 96/34; Animals; Antioxidants - administration & dosage; Antioxidants - pharmacology; Ascorbic Acid - administration & dosage; Ascorbic Acid - analogs & derivatives; Ascorbic Acid - pharmacology; Blotting, Western; Cartilage diseases; Cartilage Diseases - genetics; Cartilage Diseases - metabolism; Cartilage Diseases - prevention & control; Cartilage, Articular - drug effects; Cartilage, Articular - metabolism; Cartilage, Articular - pathology; Cells, Cultured; Chondrocytes; Chondrocytes - drug effects; Chondrocytes - metabolism; Chondrocytes - ultrastructure; Degeneration; Gene Expression - drug effects; Herbicides - pharmacology; Humanities and Social Sciences; Humans; Injections, Intra-Articular; Mechanical loading; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Microscopy, Electron; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Mitochondria - ultrastructure; multidisciplinary; Osteoarthritis; Oxidation; Paraquat - pharmacology; Reverse Transcriptase Polymerase Chain Reaction; Risk factors; Science; Stress, Mechanical; Superoxide; Superoxide dismutase; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; Superoxides - metabolism; Weight-Bearing
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/srep11722

Mechanical 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.