Mitochondrial dysfunction in osteoarthritis is associated with down‐regulation of superoxide dismutase 2

Abstract

Objective. Superoxide dismutase 2 (SOD2) is downregulated in osteoarthritis (OA). This study was undertaken to investigate the functional effects of this downregulation in the context of oxidative damage and mitochondrial dysfunction.Methods. Lipid peroxidation in articular cartilage from OA patients and from lesion-free control subjects with femoral neck fracture was assessed by measuring malondialdehyde levels using the thiobarbituric acid reactive substances assay. Long-range polymerase chain reaction amplification and a mitochondrial DNA (mtDNA) strand break assay were used to investigate the presence of somatic large-scale mtDNA rearrangements in cartilage. Microscale oxygraphy was used to explore possible changes in mitochondrial respiratory activity between OA and control chondrocytes. RNA interference was used to determine the effects of SOD2 depletion on lipid peroxidation, mtDNA damage, and mitochondrial respiration.Results. OA cartilage had higher levels of lipid peroxidation compared to control cartilage, and lipid peroxidation was similarly elevated in SOD2-depleted chondrocytes. SOD2 depletion led to a significant increase in mtDNA strand breaks in chondrocytes, but there was no notable difference in the level of strand breaks between OA and control chondrocytes. Furthermore, only very low levels of somatic, large-scale mtDNA rearrangements were identified in OA cartilage. OA chondrocytes showed less spare respiratory capacity (SRC) and higher proton leak compared to control chondrocytes. SOD2-depleted chondrocytes also showed less SRC and higher proton leak.Conclusion. This is the first study to analyze the effects of SOD2 depletion in human articular chondrocytes in terms of changes to oxidation and mitochondrial function. The findings indicate that SOD2 depletion in chondrocytes leads to oxidative damage and mitochondrial dysfunction, suggesting that SOD2 downregulation is a potential contributor to the pathogenesis of OA.Mitochondria are small organelles that are present in large (but variable) numbers in cells of all eukaryotic organisms. They have their own maternally inherited, ϳ16-kb extrachromosomal DNA, the mitochondrial genome (mtDNA), implying that mitochondrial function is regulated by both nuclear and mitochondrial transcripts (1). Mitochondria are considered the powerhouse of the cell, as they are the main sites of ATP production by oxidative phosphorylation (herein referred to as OXPHOS). Reactive oxygen species (ROS), a major by-product of OXPHOS, can act positively as signaling molecules. However, when the levels of ROS are high, this can cause oxidative damage in the form of mtDNA damage and lipid peroxidation (2). The mitochondria and the cell contain defenses against ROS, such as members of the superoxide dismutase (SOD) family (SOD1, SOD2, and SOD3), catalase, and glutathione peroxidase (3).

Targeting mitochondrial responses to intra-articular fracture to prevent posttraumatic osteoarthritis

“…This effect was prevented to varying degrees with either NAC or amobarbital treatments. We also noted that proton leakage, similar to previous observations from human arthritic tissue (11, 19), was present 6 months after IAF, was not present in cells isolated from animals receiving either NAC or amobarbital (Fig. 7E).…”

“…7C) and uncoupled maximal (Fig. 7D) oxygen consumption rates (OCRs) were increased in the cells isolated from IAF animals, similar to previously published results with chondrocytes harvested from osteoarthritic patients (11, 19). This effect was prevented to varying degrees with either NAC or amobarbital treatments.…”

“…After 6 months of normal activity after IAF, articular tissue was analyzed for proteoglycan (PG) content and mitochondrial energetic changes associated with PTOA (11, 19). The benefits of amobarbital and NAC, 6 months after any treatments were applied, included stronger safranin O staining for PG throughout the entire depth of the cartilage and within each zone, as quantified by our automated routine (n as described in Figs.…”

Duration of Symptom Relief after Intra-Articular Injection of Hyaluronic Acid Combined with Sorbitol (Anti-OX-VS) in Symptomatic HIP Osteoarthritis

“…Biochemical studies showed that free radicals have destructive effects on tissues and stimulate inflammatory processes (16,17). In the joint these substances convert hyaluronic acid directly to oligosaccharides, leading to reduction in viscosity and molecular weight.…”

Mitochondrial DNA haplogroups and ageing mechanisms in osteoarthritis

“…The increased levels of ROS also contribute to the senescence secretory phenotype, in which the age-related decline in the responses of chondrocytes to anabolic growth factors are related to increased oxidative stress 19 20. The depletion of antioxidants promotes mitochondrial dysfunction in chondrocytes,21 which in turn can amplify the stress responses through increased production of nitric oxide and ROS and activation of NF-κB signalling 21–23…”