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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.

SUBMITTER: Koike M

PROVIDER: S-EPMC4480010 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature

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

Koike Masato M Nojiri Hidetoshi H Ozawa Yusuke Y Watanabe Kenji K Muramatsu Yuta Y Kaneko Haruka H Morikawa Daichi D Kobayashi Keiji K Saita Yoshitomo Y Sasho Takahisa T Shirasawa Takuji T Yokote Koutaro K Kaneko Kazuo K Shimizu Takahiko T

Scientific reports 20150625

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 ...[more]

PMID: 26108578

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Project description:ObjectiveLumbar facet joint (LFJ) degeneration is one of the main causes of low back pain (LBP). Mechanical stress leads to the exacerbation of LFJ degeneration, but the underlying mechanism remains unknown. This study was intended to investigate the mechanism of LFJ degeneration induced by mechanical stress.MethodsHere, mice primary chondrocytes were used to screen for key microRNAs induced by mechanical overloading. SA-β-gal staining, qRT-PCR, western blot, and histochemical staining were applied to detect chondrocyte senescence in vitro and in vivo. We also used a dual-luciferase report assay to examine the targeting relationship of miRNA-325-3p (miR-325-3p) and Trp53. By using NSC-207895, a p53 activator, we investigated whether miR-325-3p down-regulated trp53 expression to reduce chondrocyte senescence. A mice bipedal standing model was performed to induce LFJ osteoarthritis. Adeno-associated virus (AAV) was intraarticularly injected to evaluate the effect of miR-325-3p on facet joint degeneration.ResultsWe observed chondrocyte senescence both in human LFJ osteoarthritis tissues and mice LFJ after bipedally standing for 10 weeks. Mechanical overloading could promote chondrocyte senescence and senescence-associated secretory phenotype (SASP) expression. MicroRNA-array analysis identified that miR-325-3p was obviously decreased after mechanical overloading, which was further validated by fluorescence in situ hybridization (FISH) in vivo. Dual-luciferase report assay showed that miR-325-3p directly targeted Trp53 to down-regulated its expression. MiR-325-3p rescued chondrocyte senescence in vitro, however, NSC-207895 reduced this effect by activating the p53/p21 pathway. Intraarticular injection of AAV expressing miR-325-3p decreased chondrocyte senescence and alleviated LFJ degeneration in vivo.ConclusionOur findings suggested that mechanical overloading could reduce the expression of miR-325-3p, which in turn activated the p53/p21 pathway to promote chondrocyte senescence and deteriorated LFJ degeneration, which may provide a promising therapeutic strategy for LFJ degeneration.

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

Publications

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

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