METTL14-mediated lncRNA-FAS-AS1 promotes osteoarthritis progression by up-regulating ADAM8

IF 2.4 4区 医学 Q2 RHEUMATOLOGY
Zhehua Zhang, Honggang Mao, Fang Li, Dahai Wang, Yan Liu
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引用次数: 0

Abstract

Background

Osteoarthritis (OA) is a prevalent degenerative disease. We explored the role and regulatory mechanisms of lncRNA-FAS-AS1 in OA progression.

Methods

We exposed human immortalized chondrocytes to IL-1β for 24 h to induce an OA cell model. The target molecule levels were assessed using western blot and quantitative real-time PCR (RT-qPCR). Cell viability and apoptosis were measured using CCK-8 and flow cytometry. The m6A modification of FAS-AS1 was determined using MeRIP. We examined the binding relationships between FAS-AS1, Fragile X mental retardation 1 (FMR1), and A disintegrin and metalloproteinase 8 (ADAM8) using RIP and RNA pull-down. The OA animal model was established by separating the medial collateral ligament and medial meniscus. Safranin-O staining and Mankin's scale were employed to evaluate pathological changes within the cartilage.

Results

FAS-AS1, METTL14, and ADAM8 were upregulated, and the JAK/STAT3 signaling pathway was activated in OA mice and IL-1β-induced chondrocytes. FAS-AS1 knockdown inhibited extracellular matrix degradation in IL-1β-induced chondrocytes; however, ADAM8 overexpression reversed this effect. FAS-AS1 maintained the stability of ADAM8 mRNA by recruiting FMR1. METTL14 knockdown repressed FAS-AS1 expression in an m6A-dependent manner. FAS-AS1 overexpression reversed the inhibitory effects of METTL14 knockdown on JAK/STAT3 signaling and cartilage damage in the OA model both in vitro and in vivo.

Conclusion

METTL14-mediated FAS-AS1 promotes OA progression through the FMR1/ADAM8/JAK/STAT3 axis.

METTL14介导的lncRNA-FAS-AS1通过上调ADAM8促进骨关节炎的进展。
背景:骨关节炎(OA)是一种常见的退行性疾病。我们探讨了lncRNA-FAS-AS1在OA进展中的作用和调控机制:方法:我们将人类永生软骨细胞暴露于 IL-1β 24 小时,以诱导 OA 细胞模型。采用 Western 印迹和定量实时 PCR(RT-qPCR)技术评估靶分子水平。使用 CCK-8 和流式细胞术检测细胞活力和凋亡。使用 MeRIP 测定了 FAS-AS1 的 m6A 修饰。我们使用 RIP 和 RNA pull-down 方法检测了 FAS-AS1、脆性 X 精神发育迟滞 1(FMR1)和 A 型崩解酶和金属蛋白酶 8(ADAM8)之间的结合关系。通过分离内侧副韧带和内侧半月板建立了 OA 动物模型。采用 Safranin-O 染色法和 Mankin 评分法评估软骨的病理变化:结果:在 OA 小鼠和 IL-1β 诱导的软骨细胞中,FAS-AS1、METTL14 和 ADAM8 被上调,JAK/STAT3 信号通路被激活。FAS-AS1敲除抑制了IL-1β诱导的软骨细胞中细胞外基质的降解;然而,ADAM8的过表达逆转了这一效应。FAS-AS1 通过招募 FMR1 维持了 ADAM8 mRNA 的稳定性。METTL14 基因敲除以 m6A 依赖性方式抑制 FAS-AS1 的表达。FAS-AS1的过表达逆转了METTL14敲除对体外和体内OA模型中JAK/STAT3信号传导和软骨损伤的抑制作用:结论:METTL14介导的FAS-AS1通过FMR1/ADAM8/JAK/STAT3轴促进OA进展。
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来源期刊
CiteScore
3.70
自引率
4.00%
发文量
362
审稿时长
1 months
期刊介绍: The International Journal of Rheumatic Diseases (formerly APLAR Journal of Rheumatology) is the official journal of the Asia Pacific League of Associations for Rheumatology. The Journal accepts original articles on clinical or experimental research pertinent to the rheumatic diseases, work on connective tissue diseases and other immune and allergic disorders. The acceptance criteria for all papers are the quality and originality of the research and its significance to our readership. Except where otherwise stated, manuscripts are peer reviewed by two anonymous reviewers and the Editor.
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