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.
Highlights
IntroductionHuman studies have previously reported that oxidative damage increased, while superoxide dismutase 2 (SOD2) protein was reciprocally downregulated in osteoarthritic degenerated cartilage
Mechanical stress and aging are major risk factors of cartilage degeneration
To reveal whether superoxide in the chondrocytes is increased under mechanical loading before obvious cartilage degeneration, superoxide generation in articular chondrocytes from both the sham surgery and destabilization of the medial meniscus (DMM) sides was evaluated at 2 weeks after surgery using dihydroethidium (DHE) and MitoSOX staining, which are detectors of intracellular and mitochondrial superoxide, respectively
Summary
Human studies have previously reported that oxidative damage increased, while SOD2 protein was reciprocally downregulated in osteoarthritic degenerated cartilage. It remains unclear whether mitochondrial superoxide imbalance in chondrocytes causes cartilage degeneration. Intra-articular injection of a permeable antioxidant effectively suppressed the mechanical loading-induced mitochondrial superoxide generation and cartilage degeneration in mice. Several studies have reported the therapeutic effect of the intra-articular injection of hyaluronic acid[3,4,5], the beneficial effect of this therapy in knee OA development was limited[3]. Wolff et al reported that cyclic dynamic loading induced superoxide generation in the chondrocytes of bovine osteochondral explants using a compression apparatus in vitro[16], suggesting that superoxide plays a pathological role in mechanical loading-induced OA development. We aim to elucidate whether abnormal loading causes a mitochondrial imbalance by Sod[2] loss in chondrocytes and whether the loss of Sod[2] or mitochondrial superoxide overproduction accelerates cartilage degeneration in mice
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