Accumulation of senescent cells has been associated with pro-inflammatory effects with deleterious consequences in different human diseases. The purpose of this study was to analyze cell senescence in human synovial tissues (ST), and its impact on the pro-inflammatory function of synovial fibroblasts (SF). The expression of the senescence marker p16INK4a (p16) was analyzed by immunohistochemistry in rheumatoid arthritis (RA), osteoarthritis (OA), and normal ST from variably aged donors. The proportion of p16(+) senescent cells in normal ST from older donors was higher than from younger ones. Although older RA and OA ST showed proportions of senescent cells similar to older normal ST, senescence was increased in younger RA ST compared to age-matched normal ST. The percentage of senescent SA-β-gal(+) SF after 14 days in culture positively correlated with donor’s age. Initial exposure to H2O2 or TNFα enhanced SF senescence and increased mRNA expression of IL6, CXCL8, CCL2 and MMP3 and proteins secretion. Senescent SF show a heightened IL6, CXCL8 and MMP3 mRNA and IL-6 and IL-8 protein expression response upon further challenge with TNFα. Treatment of senescent SF with the senolytic drug fenofibrate normalized IL6, CXCL8 and CCL2 mRNA expression. Accumulation of senescent cells in ST increases in normal aging and prematurely in RA patients. Senescence of cultured SF is accelerated upon exposure to TNFα or oxidative stress and may contribute to the pathogenesis of synovitis by increasing the production of pro-inflammatory mediators.

中文翻译：

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衰老的滑膜成纤维细胞在类风湿性关节炎组织中过早积聚并表现出增强的炎症表型


衰老细胞的积累与促炎作用有关，在不同的人类疾病中会产生有害后果。本研究的目的是分析人类滑膜组织（ST）中的细胞衰老及其对滑膜成纤维细胞（SF）促炎功能的影响。通过免疫组织化学分析不同年龄供体的类风湿性关节炎 (RA)、骨关节炎 (OA) 和正常 ST 中衰老标志物 p16INK4a (p16) 的表达。老年供体正常 ST 中 p16(+) 衰老细胞的比例高于年轻供体。尽管老年 RA 和 OA ST 的衰老细胞比例与老年正常 ST 相似，但与年龄匹配的正常 ST 相比，年轻 RA ST 的衰老程度有所增加。培养14天后SA-β-gal(+) SF的衰老百分比与供体年龄呈正相关。最初暴露于 H2O2 或 TNFα 会增强 SF 的衰老，并增加 IL6、CXCL8、CCL2 和 MMP3 的 mRNA 表达以及蛋白质分泌。进一步用 TNFα 攻击后，衰老 SF 显示出更高的 IL6、CXCL8 和 MMP3 mRNA 以及 IL-6 和 IL-8 蛋白表达反应。使用抗衰老药物非诺贝特治疗衰老 SF 可使 IL6、CXCL8 和 CCL2 mRNA 表达正常化。 ST 中衰老细胞的积累在正常衰老过程中会增加，而在 RA 患者中会过早积累。培养的 SF 暴露于 TNFα 或氧化应激后会加速衰老，并可能通过增加促炎介质的产生而促进滑膜炎的发病机制。