METTL3-mediated m6A modification of ATG7 regulates autophagy-GATA4 axis to promote cellular senescence and osteoarthritis progression

自噬 小干扰RNA 衰老 基因沉默 下调和上调 细胞生物学 骨关节炎 医学 癌症研究 污渍 转染 化学 生物 细胞培养 病理 生物化学 细胞凋亡 基因 替代医学 遗传学
作者
Xiang Chen,Wei Gong,Xiaoyan Shao,Tianshu Shi,Lei Zhang,Jian Dong,Yong Shi,Siyu Shen,Jianghui Qin,Qing Jiang,Baosheng Guo
出处
期刊:Annals of the Rheumatic Diseases [BMJ]
卷期号:81 (1): 85-97 被引量:115
标识
DOI:10.1136/annrheumdis-2021-221091
摘要

The aim of the study was to investigate the role and regulatory mechanisms of fibroblast-like synoviocytes (FLSs) and their senescence in the progression of osteoarthritis (OA).Synovial tissues from normal patients and patients with OA were collected. Synovium FLS senescence was analysed by immunofluorescence and western blotting. The role of methyltransferase-like 3 (METTL3) in autophagy regulation was explored using N6-methyladenosine (m6A)-methylated RNA and RNA immunoprecipitation assays. Mice subjected to destabilisation of the medial meniscus (DMM) surgery were intra-articularly injected with or without pAAV9 loaded with small interfering RNA (siRNA) targeting METTL3. Histological analysis was performed to determine cartilage damage.Senescent FLSs were markedly increased with the progression of OA in patients and mouse models. We determined that impaired autophagy occurred in OA-FLS, resulting in the upregulation of senescence-associated secretory phenotype (SASP). Re-establishment of autophagy reversed the senescent phenotype by suppressing GATA4. Further, we observed for the first time that excessive m6A modification negatively regulated autophagy in OA-FLS. Mechanistically, METTL3-mediated m6A modification decreased the expression of autophagy-related 7, an E-1 enzyme crucial for the formation of autophagosomes, by attenuating its RNA stability. Silencing METTL3 enhanced autophagic flux and inhibited SASP expression in OA-FLS. Intra-articular injection of synovium-targeted METTL3 siRNA suppressed cellular senescence propagation in joints and ameliorated DMM-induced cartilage destruction.Our study revealed the important role of FLS senescence in OA progression. Targeted METTL3 inhibition could alleviate the senescence of FLS and limit OA development in experimental animal models, providing a potential strategy for OA therapy.
最长约 10秒,即可获得该文献文件

科研通智能强力驱动
Strongly Powered by AbleSci AI
科研通是完全免费的文献互助平台,具备全网最快的应助速度,最高的求助完成率。 对每一个文献求助,科研通都将尽心尽力,给求助人一个满意的交代。
实时播报
刚刚
饭饭完成签到,获得积分10
2秒前
3秒前
LiueYoung应助2113采纳,获得10
4秒前
4秒前
menimeni发布了新的文献求助10
5秒前
6秒前
6秒前
明理友容发布了新的文献求助10
8秒前
Singularity应助ccqy采纳,获得10
9秒前
明亮无颜发布了新的文献求助10
11秒前
11秒前
烟花应助明理友容采纳,获得10
12秒前
12秒前
可靠青荷发布了新的文献求助10
14秒前
15秒前
sssuchzy完成签到,获得积分10
15秒前
LUNA发布了新的文献求助10
17秒前
我是AY发布了新的文献求助10
17秒前
19秒前
可靠青荷完成签到,获得积分20
19秒前
20秒前
20秒前
20秒前
中宝完成签到,获得积分10
21秒前
21秒前
24秒前
25秒前
生动以山发布了新的文献求助10
25秒前
深海鱼发布了新的文献求助10
25秒前
小脸发布了新的文献求助10
27秒前
28秒前
cooky发布了新的文献求助10
30秒前
香蕉觅云应助精明的灯泡采纳,获得10
31秒前
顾矜应助dahai采纳,获得10
32秒前
ZY发布了新的文献求助10
34秒前
35秒前
酷波er应助执着妙梦采纳,获得10
37秒前
40秒前
CodeCraft应助ZY采纳,获得10
41秒前
高分求助中
Heun’s Differential Equations 600
《Fundamentals of Power Supply Design》Robert A. Mammano 510
High Wire: How China Regulates Big Tech and Governs Its Economy 260
lingnan science journal vol. 16 250
The philosophy of sports medicine care: an historical review 250
A posteriori勾配制限手法「ポストリミタ」と界面捕獲法THINCを組み合わせた連続・不連続流れを高解像するMUSCLタイプの解法 210
Internal Flow Systems 200
热门求助领域 (近24小时)
化学 材料科学 医学 生物 有机化学 工程类 生物化学 纳米技术 物理 内科学 计算机科学 化学工程 复合材料 遗传学 基因 物理化学 催化作用 电极 光电子学 量子力学
热门帖子
关注 科研通微信公众号,转发送积分 2251222
求助须知:如何正确求助?哪些是违规求助? 1900113
关于积分的说明 4742235
捐赠科研通 1689839
什么是DOI,文献DOI怎么找? 856793
版权声明 545498
科研通“疑难数据库(出版商)”最低求助积分说明 453712