title: Mechanical overloading causes mitochondrial superoxide and SOD2 imbalance in chondrocytes resulting in cartilage degeneration.
abstract: 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.
authors.affiliation: Department of Advanced Aging Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.|Department of Orthopaedics, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Koike
authors.affiliation: Department of Orthopaedics, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Nojiri
authors.affiliation: Department of Advanced Aging Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Ozawa
authors.affiliation: Department of Advanced Aging Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Watanabe
authors.affiliation: Department of Orthopaedics, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Yuta
authors.initials: Y
authors.lastname: Muramatsu
authors.affiliation: Department of Orthopaedics, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Haruka
authors.initials: H
authors.lastname: Kaneko
authors.affiliation: Department of Orthopaedics, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Daichi
authors.initials: D
authors.lastname: Morikawa
authors.affiliation: Department of Orthopaedics, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Keiji
authors.initials: K
authors.lastname: Kobayashi
authors.affiliation: Department of Orthopaedics, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Yoshitomo
authors.initials: Y
authors.lastname: Saita
authors.affiliation: Department of Orthopaedics, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Sasho
authors.affiliation: Department of Aging Control Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Takuji
authors.initials: T
authors.lastname: Shirasawa
authors.affiliation: Department of Clinical Cell Biology and Medicine' Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Koutaro
authors.initials: K
authors.lastname: Yokote
authors.affiliation: Department of Orthopaedics, Juntendo University Graduate School of Medicine, Tokyo, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Kaneko
authors.affiliation: Department of Advanced Aging Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Shimizu
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000494:pharmacology; D001205:Ascorbic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D015153:Blotting, Western; D002357:Cartilage Diseases / Q000235:genetics / Q000378:metabolism* / Q000517:prevention & control; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D015870:Gene Expression / Q000187:drug effects; D006540:Herbicides / Q000494:pharmacology; D006801:Humans; D007270:Injections, Intra-Articular; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D010269:Paraquat / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013314:Stress, Mechanical; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism*; D016474:Weight-Bearing; D000099156:Superoxide Dismutase 2
chemical_list: D000975:Antioxidants; D001205:Ascorbic Acid; D006540:Herbicides; D010269:Paraquat; D013482:Superoxide Dismutase; D013481:Superoxides; D000099156:Superoxide Dismutase 2