METTL14介导的lncRNA-FAS-AS1通过上调ADAM8促进骨关节炎的进展。

IF 4.6 Q2 MATERIALS SCIENCE, BIOMATERIALS ACS Applied Bio Materials Pub Date : 2024-09-02 DOI:10.1111/1756-185X.15323

Zhehua Zhang, Honggang Mao, Fang Li, Dahai Wang, Yan Liu

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引用次数: 0

摘要

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

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.