The pathophysiology of rheumatoid arthritis (RA) is characterized by excess production of pro-inflammatory cytokines, including tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) by neutrophils and macrophages in synovium. Additionally, these cytokines promote the production of reactive oxygen species (ROS), and increased production of matrix metalloproteinases (MMPs), including MMP-3, in synoviocytes that result in joint destruction. There is limited information on how proteolytic enzymes such as MMP-3 can be regulated. We evaluated the effect of the antioxidant N-acetylcysteine (NAC) on RA and identified the relationship between the c-Jun N terminal kinase (JNK) pathway and MMP-3. We hypothesized that elucidating this relationship would lead to novel therapeutic approaches to RA treatment and management. We investigated the effect of administering a low dose (1000 μM or less) of an antioxidant (NAC) to human rheumatoid fibroblast-like synoviocytes (MH7A cells). We also investigated the response of antioxidant genes such as nuclear factor erythroid -derived 2-related factor 2 (Nrf2) and Sequestosome 1 (p62). The influence of MMP-3 expression on the JNK pathway leading to joint destruction and the mechanisms underlying this relationship were investigated through primary dispersion culture cells collected from the synovial membranes of RA patients, consisting of rheumatoid arthritis-fibroblast-like synoviocytes (RA-FLS). Low-dose NAC (1000 μM) increased the expression of Nrf2 and phospho-p62 in MH7A cells, activating antioxidant genes, suppressing the expression of MMP-3, and inhibiting the phosphorylation of JNK. ROS, MMP-3 expression, and IL-6 was suppressed by administering 30 μM of SP600125 (a JNK inhibitor) in MH7A cells. Furthermore, the administration of SP600125 (30 μM) to RA-FLS suppressed MMP-3. We demonstrated the existence of an MMP-3 suppression mechanism that utilizes the JNK pathway in RA-FLS. We consider that the JNK pathway could be a target for future RA therapies.

中文翻译：

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JNK途径通过抑制MMP-3代表了类风湿关节炎的新型靶标。

类风湿关节炎（RA）的病理生理学特征为过量产生促炎性细胞因子，包括肿瘤坏死因子-α（TNF-α），白介素-1β（IL-1β）和白介素-6（IL-6）。滑膜中的中性粒细胞和巨噬细胞。此外，这些细胞因子在滑膜细胞中促进活性氧（ROS）的产生，并增加基质金属蛋白酶（MMP）（包括MMP-3）的产生，导致关节破坏。关于如何调节蛋白水解酶（如MMP-3）的信息有限。我们评估了抗氧化剂N-乙酰半胱氨酸（NAC）对RA的作用，并确定了c-Jun N末端激酶（JNK）途径与MMP-3之间的关系。我们假设阐明这种关系将导致RA治疗和管理的新型治疗方法。我们研究了向人类风湿性成纤维细胞样滑膜细胞（MH7A细胞）施用低剂量（1000μM或更少）的抗氧化剂（NAC）的效果。我们还研究了抗氧化剂基因的反应，例如核因子类红细胞衍生的2相关因子2（Nrf2）和螯合1（p62）。通过从类风湿性关节炎-成纤维细胞样滑膜细胞（RA-FLS）组成的RA患者滑膜中收集的原代分散培养细胞，研究了MMP-3表达对导致关节破坏的JNK途径的影响及其相关机制。 ）。低剂量NAC（1000μM）增加MH7A细胞中Nrf2和phospho-p62的表达，激活抗氧化剂基因，抑制MMP-3的表达，并抑制JNK的磷酸化。ROS，MMP-3表达，通过在MH7A细胞中施用30μMSP600125（一种JNK抑制剂）来抑制IL-6。此外，向RA-FLS施用SP600125（30μM）可以抑制MMP-3。我们证明了存在利用RA-FLS中的JNK途径的MMP-3抑制机制。我们认为，JNK途径可能成为未来RA治疗的目标。