Background

Activated fibroblast-like synoviocyte (FLS) played a significant role in the pathogenesis and progression of rheumatoid arthritis (RA). Apigenin-4′-O-α-L-rhamnoside showed remarkable effects against RA, however, no relevant studies on pharmacology of apigenin-4′-O-α-L-rhamnoside yet, the effects and underlying molecular mechanism of apigenin-4′-O-α-L-rhamnoside on RA are still unclear.

Purpose

This study aimed to investigate the therapeutic effects and mechanisms of apigenin-4′-O-α-L-rhamnoside on RA-FLS cells by transcriptomic analysis.

Methods

In vitro, RA-FLS cell viability and migration were measured by CCK-8 and scratch assays, respectively. The effects of apigenin-4′-O-α-L-rhamnoside on inflammatory levels of MMP-1, MMP-3, RANKL and TNF-α in RA-FLS cells were detected using ELISA kits. High-throughput transcriptome analysis was performed to screen the key genes and related pathways of apigenin-4′-O-α-L-rhamnoside inhibit RA-FLSs, and the result of which were validated by RT-qPCR and western blot. Furthermore, in vivo, we also evaluated the effects of apigenin-4′-O-α-L-rhamnoside in rat with CIA.

Results

Apigenin-4′-O-α-L-rhamnoside significantly suppressed RA-FLS migration, exerted remarkable inhibiting effects on the expression levels on MMP-1, MMP3, RANKL and TNF-α in RA-FLS cells. It seemed that MAPK signaling pathway might be closely related to the pathogenesis of RA by down-regulated relevant core targets (MAPK1, HRAS, ATF-2, p38 and JNK). Moreover, apigenin-4′-O-α-L-rhamnoside attenuated the severity of arthritis in CIA rat.

Conclusion

Apigenin-4′-O-α-L-rhamnoside inhibited pro-inflammatory cytokine, chemokine and MMPs factors production of RA-FLS by targeting the MAPK signaling pathway, which provided a scientific basis for potential application in the treatment of RA.

中文翻译：

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转录组学分析揭示了芹菜素-4'-O-α-L-鼠李糖苷通过MAPK信号通路抑制类风湿性关节炎成纤维细胞样滑膜细胞活化的作用

背景

活化的成纤维样滑膜细胞（FLS）在类风湿性关节炎（RA）的发病机制和进展中起重要作用。Apigenin-4'-O-α-L-rhamnoside 对 RA 有显着疗效，但目前还没有关于 apigenin-4'-O-α-L-rhamnoside 的药理学、apigenin-4 的作用及其潜在分子机制的相关研究。 '-O-α-L-鼠李糖苷对 RA 的影响仍不清楚。

目的

本研究旨在通过转录组学分析研究芹菜素-4'-O-α-L-鼠李糖苷对RA-FLS细胞的治疗作用和机制。

方法

在体外，分别通过 CCK-8 和划痕试验测量 RA-FLS 细胞活力和迁移。ELISA试剂盒检测芹菜素4′-O- α -L-鼠李糖苷对RA-FLS细胞中MMP-1、MMP-3、RANKL和TNF-α炎症水平的影响。采用高通量转录组分析筛选芹菜素4′-O- α -L-鼠李糖苷抑制RA-FLSs的关键基因及相关通路，并通过RT-qPCR和western blot验证结果。此外，在体内，我们还评估了芹菜素-4'-O- α -L-鼠李糖苷对患有 CIA 的大鼠的作用。

结果

Apigenin-4′-O- α -L-鼠李糖苷显着抑制RA-FLS迁移，对RA-FLS细胞中MMP-1、MMP3、RANKL和TNF-α的表达水平有显着抑制作用。似乎MAPK信号通路可能通过下调相关核心靶点（MAPK1、HRAS、ATF-2、p38和JNK）与RA的发病机制密切相关。此外，芹菜素-4'-O- α -L-鼠李糖苷可减轻 CIA 大鼠关节炎的严重程度。

结论

Apigenin-4'-O- α -L-rhamnoside通过靶向MAPK信号通路抑制RA-FLS的促炎细胞因子、趋化因子和MMPs因子的产生，为潜在的RA治疗应用提供了科学依据。