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DDX5 inhibits hyaline cartilage fibrosis and degradation in osteoarthritis via alternative splicing and G-quadruplex unwinding

文献类型：期刊论文

作者Liu, Qianqian4,5; Han, Mingrui4,5,6; Wu, Zhigui7; Fu, Wenqiang9; Ji, Jun8; Liang, Qingqing8; Tan, Minjia10; Zhai, Linhui10; Gao, Jian4,5; Shi, Dongquan1
刊名NATURE AGING
出版日期2024-05-17
DOI10.1038/s43587-024-00624-0
通讯作者Xu, Qiang(qiangxu@nju.edu.cn) ; Sun, Yang(yangsun@nju.edu.cn)
英文摘要Hyaline cartilage fibrosis is typically considered an end-stage pathology of osteoarthritis (OA), which results in changes to the extracellular matrix. However, the mechanism behind this is largely unclear. Here, we found that the RNA helicase DDX5 was dramatically downregulated during the progression of OA. DDX5 deficiency increased fibrosis phenotype by upregulating COL1 expression and downregulating COL2 expression. In addition, loss of DDX5 aggravated cartilage degradation by inducing the production of cartilage-degrading enzymes. Chondrocyte-specific deletion of Ddx5 led to more severe cartilage lesions in the mouse OA model. Mechanistically, weakened DDX5 resulted in abundance of the Fn1-AS-WT and Plod2-AS-WT transcripts, which promoted expression of fibrosis-related genes (Col1, Acta2) and extracellular matrix degradation genes (Mmp13, Nos2 and so on), respectively. Additionally, loss of DDX5 prevented the unfolding Col2 promoter G-quadruplex, thereby reducing COL2 production. Together, our data suggest that strategies aimed at the upregulation of DDX5 hold significant potential for the treatment of cartilage fibrosis and degradation in OA. Liu et al. identify downregulation of DDX5, an RNA helicase, in the cartilage of patients and mouse model of osteoarthritis. Targeted upregulation of DDX5 in mouse chondrocytes inhibits hyaline cartilage fibrosis and degradation via pre-mRNA splicing and G4 unwinding, a potential therapeutic strategy against osteoarthritis.
WOS关键词RNA HELICASES ; NMR-SPECTROSCOPY ; GENE-EXPRESSION ; TRANSCRIPTION ; MECHANISMS ; PROMOTER ; REVEALS ; ELEMENT ; SWITCH ; MODEL
资助项目National Natural Science Foundation of China (National Science Foundation of China)[2022YFC3500202] ; National Key Research and Development Plan[21937005] ; National Key Research and Development Plan[82230116] ; National Key Research and Development Plan[91853109] ; National Key Research and Development Plan[81872877] ; National Key Research and Development Plan[81673436] ; National Key Research and Development Plan[32200995] ; National Natural Science Foundation of China[SIMM2205KF-14] ; Opening Foundation of the State Key Laboratory of Drug Research[2023M741642] ; China Postdoctoral Science Foundation[2023ZB212] ; Jiangsu Province Excellent Postdoctoral Program ; School of Life Science (Nanjing University) ; Mountain-Climbing Talents Project of Nanjing University
WOS研究方向Cell Biology ; Geriatrics & Gerontology ; Neurosciences & Neurology
语种英语
WOS记录号WOS:001226681100001
出版者SPRINGERNATURE
资助机构National Natural Science Foundation of China (National Science Foundation of China) ; National Key Research and Development Plan ; National Natural Science Foundation of China ; Opening Foundation of the State Key Laboratory of Drug Research ; China Postdoctoral Science Foundation ; Jiangsu Province Excellent Postdoctoral Program ; School of Life Science (Nanjing University) ; Mountain-Climbing Talents Project of Nanjing University
源URL[http://ir.hfcas.ac.cn:8080/handle/334002/136842]  
专题中国科学院合肥物质科学研究院
通讯作者Xu, Qiang; Sun, Yang
作者单位1.Nanjing Univ, Med Sch, Nanjing Drum Tower Hosp, Dept Sports Med & Adult Reconstruct Surg,Affiliate, Nanjing, Peoples R China
2.Nanjing Univ, Jinling Hosp, Med Sch, Dept Orthopaed,Affiliated Hosp, Nanjing, Peoples R China
3.East China Normal Univ, Sch Life Sci, Shanghai Key Lab Regulatory Biol, Shanghai, Peoples R China
4.Nanjing Univ, State Key Lab Pharmaceut Biotechnol, Med Sch, Nanjing Drum Tower Hosp,Affiliated Hosp,Sch Life S, Nanjing, Peoples R China
5.Nanjing Univ, Sch Life Sci, Nanjing Drum Tower Hosp, Dept Sports Med & Adult Reconstruct Surg,,Affiliat, Nanjing, Peoples R China
6.Xuzhou Med Univ, Jiangsu Key Lab New Drug Res & Clin Pharm, Xuzhou, Peoples R China
7.Peking Univ, Acad Adv Interdisciplinary Studies, Peking Tsinghua Ctr Life Sci, Beijing, Peoples R China
8.Nanjing Univ, Nanjing Stomatol Hosp, Affiliated Hosp, Med Sch, Nanjing, Peoples R China
9.Chinese Acad Sci, High Magnet Field Lab, Hefei, Peoples R China
10.Chinese Acad Sci, State Key Lab Drug Res, Shanghai Inst Mat Med, Shanghai, Peoples R China
推荐引用方式
GB/T 7714		 Liu, Qianqian,Han, Mingrui,Wu, Zhigui,et al. DDX5 inhibits hyaline cartilage fibrosis and degradation in osteoarthritis via alternative splicing and G-quadruplex unwinding[J]. NATURE AGING,2024.
APA Liu, Qianqian.,Han, Mingrui.,Wu, Zhigui.,Fu, Wenqiang.,Ji, Jun.,...&Sun, Yang.(2024).DDX5 inhibits hyaline cartilage fibrosis and degradation in osteoarthritis via alternative splicing and G-quadruplex unwinding.NATURE AGING.
MLA Liu, Qianqian,et al."DDX5 inhibits hyaline cartilage fibrosis and degradation in osteoarthritis via alternative splicing and G-quadruplex unwinding".NATURE AGING (2024).

入库方式： OAI收割

来源：合肥物质科学研究院

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