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.

BackgroundOsteoarthritis (OA) is a multifactorial disease characterized by destruction of the articular cartilage due to environmental, mechanical and genetic components. The genetics of OA is complex and is not completely understood. Recent works have demonstrated the importance of microRNAs (miRNAs) in cartilage function. MiRNAs are a class of small noncoding RNAs that regulate gene expression and are involved in different cellular process: apoptosis, proliferation, development, glucose and lipid metabolism. The aim of this study was to identify and characterize the expression profile of miRNAs in normal and OA chondrocytes and to determine their role in the OA.MethodsChondrocytes were moved to aggregate culture and evaluated using histological and qPCR techniques. miRNAs were isolated and analyzed using the Agilent Human miRNA Microarray.ResultsOf the 723 miRNAs analyzed, 7 miRNAs showed a statistically significant differential expression. Amongst these 7 human miRNAs, 1 was up-regulated in OA chondrocytes (hsa-miR-483-5p) and 6 were up-regulated in normal chondrocytes (hsa-miR-149*, hsa-miR-582-3p, hsa-miR-1227, hsa-miR-634, hsa-miR-576-5p and hsa-miR-641). These profiling results were validated by the detection of some selected miRNAs by qPCR. In silico analyses predicted that key molecular pathways potentially altered by the miRNAs differentially expressed in normal and OA chondrocytes include TGF-beta, Wnt, Erb and mTOR signalling; all of them implicated in the development, maintenance and destruction of articular cartilage.ConclusionsWe have identified 7 miRNAs differentially expressed in OA and normal chondrocytes. Our potential miRNA target predictions and the signalling cascades altered by the differentially expressed miRNAs supports the potential involvement of the detected miRNAs in OA pathology. Due to the importance of miRNA in mediating the translation of target mRNA into protein, the identification of these miRNAs differentially expressed in normal and OA chondrocyte micropellets could have important diagnostic and therapeutic potential. Further studies are needed to know the function of these miRNAs, including the search of their target mRNA genes, which could lead to the development of novel therapeutic strategies for the OA treatment.

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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-

Osteoarthritis (OA) is the most common rheumatic pathology. Because currently available diagnostic methods are limited and lack sensitivity, the identification of new specific biological markers for OA has become a focus. The purpose of this study was to identify novel protein biomarkers for moderate and severe OA in serum. Sera were obtained from 50 moderate OA patients, 50 severe OA patients, and 50 nonsymptomatic controls. Serum protein levels were analyzed using isobaric tags for relative and absolute quantitation (iTRAQ) and matrix-assisted laser desorption/ionization (MALDI)-TOF/TOF mass spectrometry. We identified 349 different proteins in the sera, 262 of which could be quantified by calculation of their iTRAQ ratios. Three sets of proteins were significantly (p < 0.05) changed in OA samples compared to controls. Of these, 6 were modulated only in moderate OA, 13 only in severe OA and 7 in both degrees. Although some of these proteins, such as cartilage oligomeric matrix protein, have a previously reported putative biomarker value for OA, most are novel biomarker candidates for the disease. These include some complement components, lipoproteins, von Willebrand factor, tetranectin, and lumican. The specificity and selectivity of these candidates need to be validated before new molecular diagnostic or prognostic tests for OA can be developed.

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.

The results of this study support the hypothesis that the mtDNA haplogroups have a role in the complex osteoarthritic process.

Methods: Observational, open-label multicenter study from 40 national referral centers of GCA patients treated with TCZ due to inefficacy or adverse events of previous therapy. Outcomes variables were improvement of clinical features, acute phase reactants, glucocorticoid-sparing effect, prolonged remission and relapses. A comparative study was performed: a) TCZ route (SC vs. IV); b) GCA duration (≤6 vs. >6 months); c) serious infections (with or without); d) ≤15 vs. >15 mg/day at TCZ onset. Results: 134 patients; mean age, 73.0±8.8 years. TCZ was started after a median [IQR] time from GCA diagnosis of 13.5 [5.0-33.5] months. Ninety-eight (73.1%) patients had received immunosuppressive agents. After 1 month of TCZ 93.9% experienced clinical improvement. Reduction of CRP from 1.7 [0.4-3.2] to 0.11 [0.05-0.5] mg/dL (p<0.0001), ESR from 33 [14.5-61] to 6 [2-12] mm/1 st hour (p<0.0001) and decrease in patients with anemia from 16.4% to 3.8% (p<0.0001) were observed. Regardless of administration route or disease duration, clinical improvement leading to remission at 6, 12, 18, 24 months was observed in 55.5%, 70.4%, 69.2% and 90% of patients. Most relevant adverse side-effect was serious infections (10.6/100 patients-year), associated with higher doses of prednisone during the first three months of therapy. Conclusion: In clinical practice, TCZ yields a rapid and maintained improvement of refractory GCA. Serious infections appear to be higher than in clinical trials.