Department of Clinical Nutrition, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China.
Department of Nutrition and Food Hygiene, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, China.
Clin Exp Rheumatol. 2024 Jul;42(7):1387-1397. doi: 10.55563/clinexprheumatol/3pd9rp. Epub 2024 Jul 8.
The imbalance between apoptosis and proliferation in fibroblast-like synoviocytes (FLSs) plays a key role in the pathogenesis of rheumatoid arthritis (RA). This study aims to investigate the potential of all-trans retinoic acid (ATRA) as a supplementary therapeutic agent alongside methotrexate (MTX) for RA, by examining its ability to inhibit synovial cell proliferation and enhance apoptosis through the ROS-JNK signalling pathway.
The viability, apoptosis, and autophagy levels of human rheumatoid arthritis fibroblast-like synovial cells (HFLS-RA) were evaluated, while ROS generation was measured through the DCFH-DA fluorescence microplate assay. Western blotting was used to analyse the expression levels of JNK signalling pathway-related proteins. To assess therapeutic potential in vivo, a collagen-induced arthritis (CIA) model was established in Wistar rats.
Small doses of MTX did not significantly affect the viability of HFLS-RAs or induce apoptosis. However, when ATRA was added to the treatment, the therapy markedly inhibited cell proliferation and induced apoptosis and excessive autophagy. Mechanistically, ATRA activated the ROS/JNK signalling pathway in HFLS-RAs. ROS scavengers and JNK inhibitors significantly attenuated ATRA-induced apoptosis and autophagy. In vivo, the combination therapy demonstrated a remarkable enhancement of the anti-arthritic efficacy in CIA rats.
The ability of ATRA to inhibit proliferation in RA FLSs through autophagy and apoptosis underscores its potential as a supplementary therapeutic agent alongside MTX for RA, particularly when compared to the limited impact of MTX on these processes. This combined strategy holds promise for enhancing therapeutic outcomes and warrants further investigation in the management of RA.
成纤维样滑膜细胞（FLS）中凋亡与增殖失衡在类风湿关节炎（RA）发病机制中起关键作用。本研究旨在通过研究全反式维甲酸（ATRA）通过 ROS-JNK 信号通路抑制滑膜细胞增殖和增强凋亡的能力，探讨其作为甲氨蝶呤（MTX）治疗 RA 的辅助治疗药物的潜力。
评估人类风湿关节炎成纤维样滑膜细胞（HFLS-RA）的活力、凋亡和自噬水平，通过 DCFH-DA 荧光微孔板测定 ROS 的产生。Western blot 分析 JNK 信号通路相关蛋白的表达水平。在胶原诱导性关节炎（CIA）大鼠模型中评估体内治疗潜力。
小剂量 MTX 对 HFLS-RAs 的活力没有显著影响，也不会诱导凋亡。然而，当 ATRA 加入治疗时，治疗明显抑制细胞增殖并诱导凋亡和过度自噬。机制上，ATRA 在 HFLS-RAs 中激活了 ROS/JNK 信号通路。ROS 清除剂和 JNK 抑制剂显著减弱了 ATRA 诱导的凋亡和自噬。在体内，联合治疗在 CIA 大鼠中显著增强了抗关节炎疗效。
ATRA 通过自噬和凋亡抑制 RA FLSs 增殖的能力突显了其作为 MTX 治疗 RA 的辅助治疗药物的潜力，尤其是与 MTX 对这些过程的有限影响相比。这种联合策略有望提高治疗效果，值得进一步研究用于 RA 的治疗。
