Objective Alterations in DNA methylation patterns have been found to correlate with several diseases including osteoarthritis (OA). The aim of this study was to identify, for the first time, the genome-wide DNA methylation profiles of human articular chondrocytes from OA cartilage and healthy control cartilage samples. Methods DNA methylation profiling was performed using Illumina Infinium HumanMethylation27 in 25 patients with OA and 20 healthy controls. Subsequent validation was performed by genome-wide expression analysis using the Affymetrix Human Gene 1.1 ST array in an independent cohort of 24 patients with OA. Finally, the most consistent genes in both assays were amplified by quantitative reverse transcriptase PCR in a validation cohort of 48 patients using microfluidic real-time quantitative PCR. Appropriate bioinformatics analyses were carried out using R bioconductor software packages and qBase plus software from Biogazelle. Results We found 91 differentially methylated (DM) probes, which permitted us to separate patients with OA from healthy controls. Among the patients with OA, we detected 1357 DM probes that identified a tight cluster of seven patients who were different from the rest. This cluster was also identified by genome-wide expression in which 450 genes were differentially expressed. Further validation of the most consistent genes in an independent cohort of patients with OA permitted us to identify this cluster, which was characterised by increased inflammatory processes. Conclusions We were able to identify a tight subgroup of patients with OA, characterised by an increased inflammatory response that could be regulated by epigenetics. The identification and isolation of this subgroup may be critical for the development of effective treatment and disease prevention.

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 radiographs had previously been classified as grades 1–4 according to Kellgren/Lawrence (K/L) scoring system.Results: Individuals carrying haplogroup J showed a significantly decreased risk of knee OA (odds ratio [OR] 0.460 [95% confidence interval (95% CI) 0.282–0.748], P = 0.002). In terms of K/L scores, patients carrying haplogroup J had a less severe progression of knee OA (OR 0.351 [95% CI 0.156–0.787], P = 0.012), while those carrying haplogroup U had a more severe progression (OR 1.788 [95% CI 1.094–2.922], P = 0.025).Conclusion: People carrying haplogroup J may be at a lower risk of developing knee OA, and those carrying this haplogroup in whom knee OA does not develop may have a less severe progression of the disease. Patients with knee OA carrying haplogroup U may have a more severe progression of the disease. These results indicate that mtDNA haplogroups contribute to the pathogenesis of OA.

Objective To evaluate the influence of the mitochondrial DNA (mtDNA) haplogroups in the risk of incident knee osteoarthritis (OA) and to explain the functional consequences of this association to identify potential diagnostic biomarkers and therapeutic targets. Methods Two prospective cohorts contributed participants. The osteoarthritis initiative (OAI) included 2579 subjects of the incidence subcohort, and the cohort hip and cohort knee (CHECK) included 635, both with 8-year follow-up. The analysis included the association of mtDNA haplogroups with the rate of incident knee OA in subjects from both cohorts followed by a subsequent meta-analysis. Transmitochondrial cybrids harbouring haplogroup J or H were constructed to detect differences between them in relation to physiological features including specific mitochondrial metabolic parameters, reactive oxygen species production, oxidative stress and apoptosis. Results Compared with H, the haplogroup J associates with decreased risk of incident knee OA in subjects from OAI (HR=0.680; 95% CI 0.470 to 0.968; p<0.05) and CHECK (HR=0.728; 95% CI 0.469 to 0.998; p<0.05). The subsequent meta-analysis including 3214 cases showed that the haplogroup J associates with a lower risk of incident knee OA (HR=0.702; 95% CI 0.541 to 0.912; p=0.008). J cybrids show a lower free radical production, higher cell survival under oxidative stress conditions, lower grade of apoptosis as well as lower expression of the mitochondrially related pro-apoptotic gene BCL2 binding component 3 (BBC3). In addition, J cybrids also show a lower mitochondrial respiration and glycolysis leading to decreased ATP production. Conclusions The physiological effects of the haplogroup J are beneficial to have a lower rate of incident knee OA over time. Potential drugs to treat OA could focus on emulating the mitochondrial behaviour of this haplogroup.

Osteoarthritis is a degenerative articular disease with complex pathogeny because diverse factors interact causing a process of deterioration of the cartilage. Despite the multifactorial nature of this pathology, from the 50's it s known that certain forms of osteoarthritis are related to a strong genetic component. The genetic bases of this disease do not follow the typical patterns of mendelian inheritance and probably they are related to alterations in multiple genes. The identification of a high number of candidate genes to confer susceptibility to the development of the osteoarthritis shows the complex nature of this disease. At the moment, the genetic mechanisms of this disease are not known, however, which seems clear is that expression levels of several genes are altered, and that the inheritance will become a substantial factor in future considerations of diagnosis and treatment of the osteoarthritis.

To analyse the mitochondrial DNA (mtDNA) haplogroups of patients with hip osteoarthritis (OA) and those of healthy controls in a Spanish population. mtDNA haplogroups were assigned to 550 cases of hip OA and 505 clinically asymptomatic controls. Sets of controls with healthy knees and hips (n = 179) and patients with knee and/or hip OA (n = 977) were also analysed in a multivariate analysis after adjusting for sex, age and smoking. Individuals carrying haplogroup J showed a significantly decreased risk of developing hip OA (OR 0.661; 95% CI 0.440 to 0.993; p = 0.045). In addition to haplogroup J, smoking protected against the development of hip OA (OR 0.543; 95% CI 0.311 to 0.946; p = 0.031). However, no relationship was found between rheumatoid arthritis and mtDNA haplogroups. The results of this study support the hypothesis that the mtDNA haplogroups have a role in the complex osteoarthritic process.

Background: Oxidative stress play a main role in the initiation and progression of the OA disease and leads to the degeneration of mitochondria. To prevent this, the chondrocytes possess a well-coordinated enzymatic antioxidant system. Besides, the mitochondrial DNA (mtDNA) haplogroups are associated with the OA disease. Thus, the main goal of this work is to assess the incidence of the mtDNA haplogroups on serum levels of two of the main antioxidant enzymes, Manganese Superoxide Dismutase (Mn-SOD or SOD2) and catalase, and to test the suitability of these two proteins for potential OA-related biomarkers. Methods: We analyzed the serum levels of SOD2 and catalase in 73 OA patients and 77 healthy controls carrying the haplogroups J, U and H, by ELISA assay. Knee and hip radiographs were classified according to Kellgren and Lawrence (K/L) scoring from Grade 0 to Grade IV. Appropriate statistical analyses were performed to test the effects of clinical variables, including gender, body mass index (BMI), age, smoking status, diagnosis, haplogroups and radiologic K/L grade on serum levels of these enzymes. Results: Serum levels of SOD2 appeared statistically increased in OA patients when compared with healthy controls (p < 0.001). Even in those OA patients with higher OA severity (K/L grade IV), the serum levels of this antioxidant enzyme appeared more significantly increased than in OA patients with lower K/L grade (p < 0.001). The mtDNA haplogroups showed an influence on serum levels of catalase (p = 0.054), being carriers of the mtDNA haplogroup J those who showed higher serum levels than non-J carriers (p = 0.057). Conclusions: The increased levels of SOD2 in OA patients indicate an increased oxidative stress OA-related, therefore this antioxidant enzyme could be a suitable candidate biomarker for diagnosis of OA. Mitochondrial haplogroups significantly correlates with serum levels of catalase