Accumulation of mitochondrial DNA with 4977-bp deletion in knee cartilage – an association with idiopathic osteoarthritis

Chang, Ming-Chau; Hung, Shih‐Chieh; Chen, Winby York-Kwan; Chen, Tzu-Ling; Lee, Cheng-Feng; Wang, Kaili; Chiou, Chung-Chih; Wei, Yau‐Huei

doi:10.1016/j.joca.2005.06.011

Cited by 29 publications

(16 citation statements)

References 46 publications

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“…Although 2 reports have analyzed the presence of mtDNA somatic mutations in OA articular chondrocytes (39,40), to date, no studies have shown a possible association between mtDNA mutations and OA. In this study, we present the first evidence that the European mtDNA haplogroup J is involved in conferring protection from the incidence and severity of knee OA, while mtDNA haplogroup U appears to be associated with an increase in the radiologic severity of knee OA.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA haplogroups: Role in the prevalence and severity of knee osteoarthritis

Rego‐Pérez¹,

Fernández-Moreno²,

Fernández-López³

et al. 2008

Arthritis & Rheumatism

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Objective. Some studies indicate that the mitochondrion is implicated in osteoarthritis (OA). To test the hypothesis that mitochondrial DNA (mtDNA) haplogroups contribute to the prevalence and severity of knee OA, we analyzed the European mtDNA haplogroups in a Spanish population of patients with knee OA and healthy control subjects.Methods. We combined the single-base extension assay with the polymerase chain reaction-restriction fragment length polymorphism technique to obtain the different single-nucleotide polymorphisms that characterize the European haplogroups in 457 patients with knee OA and 262 radiologic controls. Knee OA radio-

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Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA haplogroups: Role in the prevalence and severity of knee osteoarthritis

Rego‐Pérez¹,

Fernández-Moreno²,

Fernández-López³

et al. 2008

Arthritis & Rheumatism

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“…Continuous oxidative stress such as this can lead to cartilage degradation via mitochondria damage, enhanced lipid peroxidation [8–10]. The ability of OA patients to respond to this stress is also compromised, with oxidant scavenging enzymes, such as superoxide dismutase, significantly decreased in OA chondrocytes, as compared to normal chondrocytes [11,12].…”

Section: Introductionmentioning

confidence: 99%

Eupatilin Exerts Antinociceptive and Chondroprotective Properties in a Rat Model of Osteoarthritis by Downregulating Oxidative Damage and Catabolic Activity in Chondrocytes

et al. 2015

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Increases in oxidative stress are thought to be associated with the development of osteoarthritis (OA). Eupatilin, one of the major compounds present in artemisia species, was shown to have both anti-oxidative and anti-inflammatory properties. Here, we investigated the in vivo effects of eupatilin on pain severity and cartilage degradation in an experimental rat model of OA, along with the mechanisms of action underlying these effects. Experimental OA was induced via an intra-articular injection of monosodium iodoacetate (MIA), with oral administration of eupatilin initiated on the day of MIA injection. Pain was assessed by measuring the paw withdrawal latency and threshold. Cartilage destruction was analyzed macroscopically and histomorphologically. The effects of eupatilin on mRNA expression were investigated in interleukin-1β (IL-1β)-stimulated human OA chondrocytes. Eupatilin treatment exhibited clear antinociceptive effects, along with an attenuation of cartilage degradation in OA rats. Additionally, the number of osteoclasts present in the subchondral bone region was significantly decreased following eupatilin treatment. Eupatilin reduced the expression of interleukin-1β (IL-1β), interleukin-6 (IL-6), nitrotyrosine and inducible nitric oxide synthase (iNOS) in cartilage. mRNA levels of matrix metalloproteinase-3 (MMP-3), MMP13, and a disintegrin and metalloproteinase with thrombospondin motifs-5 (ADAMTS-5) were reduced in IL-1β-stimulated human OA chondrocytes, while tissue inhibitor of metalloproteinases-1 (TIMP-1) was induced. Phosphorylated protein levels of the c-jun N-terminal kinase (JNK) was reduced by eupatilin. Taken together, these results suggest that eupatilin suppresses oxidative damage and reciprocally enhances extracellular matrix production in articular chondrocytes, making eupatilin a promising therapeutic option for the treatment of OA.

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“…High levels of ROS can lead to increased levels of mtDNA damage (9, 10), greater lipid peroxidation, and also activation of signaling pathways, all of which can exacerbate cartilage degradation (11, 12). In addition, high levels of ROS can lead to the cleavage of collagen and hyaluronan (13, 14).…”

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confidence: 99%

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

Gavriilidis¹,

Miwa²,

Zglinicki³

et al. 2013

Arthritis & Rheumatism

127

122

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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).

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Accumulation of mitochondrial DNA with 4977-bp deletion in knee cartilage – an association with idiopathic osteoarthritis

Abstract: The results suggest that accumulation of the 4977-bp deletion of mtDNA in knee cartilage increases with age and may play a role in the development of idiopathic OA in the knee joint.

Cited by 29 publications

References 46 publications

Mitochondrial DNA haplogroups: Role in the prevalence and severity of knee osteoarthritis

Mitochondrial DNA haplogroups: Role in the prevalence and severity of knee osteoarthritis

Eupatilin Exerts Antinociceptive and Chondroprotective Properties in a Rat Model of Osteoarthritis by Downregulating Oxidative Damage and Catabolic Activity in Chondrocytes

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

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