title: E2 regulates MMP-13 via targeting miR-140 in IL-1β-induced extracellular matrix degradation in human chondrocytes.
abstract: Estrogen deficiency is closely related to the development of menopausal arthritis. Estrogen replacement therapy (ERT) shows a protective effect against the osteoarthritis. However, the underlying mechanism of this protective effect is unknown. This study aimed to determine the role of miR-140 in the estrogen-dependent regulation of MMP-13 in human chondrocytes.
  
  
  
  Primary human articular chondrocytes were obtained from female OA patients undergoing knee replacement surgery. Normal articular chondrocytes were isolated from the knee joints of female donors after trauma and treated with interleukin-1 beta (IL-1β). Gene expression levels of miR-140, MMP-13, and ADAMTS-5 were detected by quantitative real-time PCR (qRT-PCR). miR-140 levels were upregulated or downregulated by transfecting cells with a miRNA mimic and inhibitor, respectively, prior to treatment with IL-1β. MMP-13 expression was then evaluated by Western blotting and immunofluorescence. Luciferase reporter assays were performed to verify the interaction between miR-140 and ER.
  
  
  
  17-β-estradiol (E2) suppressed MMP-13 expression in human articular chondrocytes. miR-140 expression was upregulated after estrogen treatment. Knockdown of miR-140 expression abolished the inhibitory effect of estrogen on MMP-13. In addition, the estrogen/ER/miR-140 pathway showed an inhibitory effect on IL-1β-induced cartilage matrix degradation.
  
  
  
  This study suggests that estrogen acts via ER and miR-140 to inhibit the catabolic activity of proteases within the chondrocyte extracellular matrix. These findings provide new insight into the mechanism of menopausal arthritis and indicate that the ER/miR-140 signaling pathway may be a potential target for therapeutic interventions for menopausal arthritis.
authors.affiliation: School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, Guangdong Province, China.|Departments of Chemistry, The Chinese University of Hong Kong, Shatin, Hong Kong, SAR, China.|Shenzhen Key Laboratory of Tissue Engineering, Shenzhen Second People's Hospital (The First Hospital Affiliated to Shenzhen University), Shenzhen, 518035, Guangdong Province, China.
authors.forename: Yujie
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Shenzhen Key Laboratory of Tissue Engineering, Shenzhen Second People's Hospital (The First Hospital Affiliated to Shenzhen University), Shenzhen, 518035, Guangdong Province, China.|Department of Orthopedics, Shenzhen Second People's Hospital (The First Hospital Affiliated to Shenzhen University), Shenzhen, 518035, Guangdong Province, China.
authors.forename: Li
authors.initials: L
authors.lastname: Duan
authors.affiliation: Shenzhen Key Laboratory of Tissue Engineering, Shenzhen Second People's Hospital (The First Hospital Affiliated to Shenzhen University), Shenzhen, 518035, Guangdong Province, China.|Department of Orthopedics, Shenzhen Second People's Hospital (The First Hospital Affiliated to Shenzhen University), Shenzhen, 518035, Guangdong Province, China.
authors.forename: Jianyi
authors.initials: J
authors.lastname: Xiong
authors.affiliation: Shenzhen Key Laboratory of Tissue Engineering, Shenzhen Second People's Hospital (The First Hospital Affiliated to Shenzhen University), Shenzhen, 518035, Guangdong Province, China.|Department of Orthopedics, Shenzhen Second People's Hospital (The First Hospital Affiliated to Shenzhen University), Shenzhen, 518035, Guangdong Province, China.
authors.forename: Weiming
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Shenzhen Key Laboratory of Tissue Engineering, Shenzhen Second People's Hospital (The First Hospital Affiliated to Shenzhen University), Shenzhen, 518035, Guangdong Province, China.|Department of Orthopedics, Shenzhen Second People's Hospital (The First Hospital Affiliated to Shenzhen University), Shenzhen, 518035, Guangdong Province, China.
authors.forename: Qisong
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Shenzhen Key Laboratory of Tissue Engineering, Shenzhen Second People's Hospital (The First Hospital Affiliated to Shenzhen University), Shenzhen, 518035, Guangdong Province, China.|Department of Orthopedics, Shenzhen Second People's Hospital (The First Hospital Affiliated to Shenzhen University), Shenzhen, 518035, Guangdong Province, China.
authors.forename: Daming
authors.initials: D
authors.lastname: Wang
authors.affiliation: Shenzhen Key Laboratory of Tissue Engineering, Shenzhen Second People's Hospital (The First Hospital Affiliated to Shenzhen University), Shenzhen, 518035, Guangdong Province, China.|Department of Orthopedics, Shenzhen Second People's Hospital (The First Hospital Affiliated to Shenzhen University), Shenzhen, 518035, Guangdong Province, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, Guangdong Province, China. lizg@pkusz.edu.cn.
authors.forename: Zigang
authors.initials: Z
authors.lastname: Li
authors.affiliation: Shenzhen Key Laboratory of Tissue Engineering, Shenzhen Second People's Hospital (The First Hospital Affiliated to Shenzhen University), Shenzhen, 518035, Guangdong Province, China. DapingWang1963@qq.com.|Department of Orthopedics, Shenzhen Second People's Hospital (The First Hospital Affiliated to Shenzhen University), Shenzhen, 518035, Guangdong Province, China. DapingWang1963@qq.com.
authors.forename: Daping
authors.initials: D
authors.lastname: Wang
mesh_terms: D015153:Blotting, Western; D002358:Cartilage, Articular / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D006801:Humans; D053583:Interleukin-1beta / Q000378:metabolism; D053509:Matrix Metalloproteinase 13 / Q000096:biosynthesis*; D035683:MicroRNAs / Q000378:metabolism*; D020370:Osteoarthritis, Knee / Q000378:metabolism* / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D059467:Transcriptome
chemical_list: D047628:Estrogen Receptor alpha; D053583:Interleukin-1beta; D035683:MicroRNAs; C544302:Mirn140 microRNA, human; D004958:Estradiol; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13
keywords: Estrogen; MMP-13; Menopausal arthritis; miR-140