BackgroundAccumulating evidence implicates hypoxia in the pathogenesis of rheumatoid arthritis (RA). The effect of hypoxia on the expression of Slug, a transcriptional repressor that impairs apoptosis of RA fibroblast-like synoviocytes (FLS), remains unknown.ObjectivesThe aim of this study is to investigate the role of hypoxia in the expression of Slug in RA FLS and to delineate the signaling pathway involved in the process.MethodsAfter RA FLS were exposed to hypoxia, expression of HIF1-a and phosphorylation of ERK, JNK, and STAT3 were analyzed by Western blot. The experiment was repeated with RA FLS pretreated with WP1066, an inhibitor of the JAK/STAT pathway. RT-PCR was performed to measure HIF-1a mRNA and Slug mRNA expressions in RA FLS under hypoxia. RA FLS was transfected with HIF-1a cDNA to investigate the effect of overexpression of HIF-a on Slug expression. Immunohistochemistry was used to assess the presence HIF-1a and Slug in RA synovial tissue. Microarray analysis was performed to investigate the change in Slug gene expression when FLS were exposed to hypoxia. Finally, the effect of TNF-α on Slug and HIF-1α expressions under normoxic conditions was assessed in RA FLS by Western blot.ResultsHypoxia induced the expression of HIF-1a and phosphorylation of STAT3, but not JNK and ERK was increased in RA FLS. Pre-treatment of RA FLS with WP1066 before exposure to hypoxia inhibited the expression of p-STAT and HIF-1a. Hypoxic conditions induced Slug mRNA expression from RA FLS, and similarly, overexpression of HIF-1a in RA FLS reproduced enhanced Slug expression. Microarray analysis revealed a significantly up-regulated Slug expression. Immunohistochemical staining showed that HIF-1a and Slug were co-localized in the lining area of RA synovium. Stimulation of FLS with TNF-α alone without hypoxia resulted in increased expression of Slug HIF-1a and Slug.ConclusionsOur study demonstrates that HIF-1a expression from RA FLS induced by hypoxia or TNF-a alone is mediated through JAK/STAT3 signaling pathway, which ultimately leads to the expression of Slug. Hypoxia-driven pathway of Slug expression may become a novel treatment target in RA.Disclosure of InterestNone declared
BackgroundRheumatoid arthritis (RA) is a chronic, inflammatory disease that mainly affects the synovial joints. Metabolomics, which is defined as the comprehensive analysis of the small-molecule metabolites in a biological system, is a rapidly developing approach in biomarker research.ObjectivesThis study was to determine whether there is variation in the synovial fluid (SF) metabolome in RA patients according to the degree of disease activity using gas chromatography/time-of-flight-mass spectrometry (GC/TOF-MS), in order to gain more insight into the pathologic metabolic alterations in RA.MethodsSF samples were analysed in 47 patients with active RA, divided into moderately active- (2.8
BackgroundRheumatoid arthritis (RA) treatment may differ according to hepatitis B state and consequently bring about different outcome of arthritis. Only a small number of studies have addressed the differences in disease characteristics and treatment patterns of RA in relation to hepatitis B state. However, it has not yet been elucidated whether hepatitis B affects treatment outcome such as disease activity.ObjectivesWe investigated possible differences in change of arthritis activity between RA patients according to concomitant hepatitis B virus (HBV) infection.MethodsA retrospective analysis of 40 hepatitis B surface antigen (HBsAg)-positive RA patients and 112 HBsAg-negative RA patients was conducted. The longitudinal relationship between HBsAg-positivity and RA activity/medication use was analyzed using generalized estimating equations in regression models.ResultsThere were no significant differences in group for baseline characteristics. In regression analysis, RA activity-related outcomes showed follow-up time-dependent improvement during study period. We observed significant interaction between time and HBsAg-positivity for disease activity score in 28 joints with 3 variables (DAS28–3; P =0.026), that means decreases in DAS28–3 with time influenced by HBsAg-positivity. But this interaction did not remain significant after adjustment. For tender joints, erythrocyte sedimentation rate, and C-reactive protein levels, there were no interaction between time and HBsAg-positivity, while swollen joints showed significant interaction (P =0.017). The time-association and group differences were not observed in alanine aminotransferase (ALT) level. Over all visits, HBsAg-positive patients were less likely to receive methotrexate (OR 0.09 [95% CI 0.04–0.19], P <0.0001) and more likely to receive sulfasalazine (OR 3.67 [95% CI 1.94–6.95], P <0.0001). In HBsAg-positive RA patients, initial hepatitis B state was related to use of DMARDs, especially methotrexate (P =0.040). Hepatitis reactivation occurred in 4 patients (10%) in HBsAg-positive RA patients. Among the patients who experienced HBV reactivation, only one patient had received previous antiviral treatment at baseline, but the patient exhibited lower adherence to drug. All patients who experienced HBV reactivation showed positive HBV DNA at baseline. There were no cases of hepatic failure or death.ConclusionsThere were no significant differences over time in DAS28–3, tender joints, inflammatory markers, according to HBsAg-positivity, while swollen joints showed significant difference over time. ALT level did not showed time-association and group differences. HBsAg-positive RA patients were less likely to receive methotrexate and more likely to receive sulfasalazine.Disclosure of InterestNone declared
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