title: The IL-1β/AP-1/miR-30a/ADAMTS-5 axis regulates cartilage matrix degradation in human osteoarthritis.
abstract: The proinflammatory cytokine interleukin-1β (IL-1β) is involved in the initiation and progression of osteoarthritis (OA) by stimulating the expression of matrix-degrading proteinases, such as a disintegrin metalloproteinase with thrombospondin motifs-5 (ADAMTS-5), a key player in OA pathogenesis. However, how IL-1β induces ADAMTS-5 overexpression is poorly understood. We demonstrate that IL-1β regulates ADAMTS-5 expression by suppressing microRNA-30a (miR-30a). Bioinformatics was performed to predict miRNAs targeting ADAMTS-5. miR-30a inhibited ADAMTS-5 expression by directly targeting its 3'-untranslated region. miR-30a expression was downregulated in OA patients and was negatively correlated with ADAMTS-5 expression and positively correlated with Hospital for Special Surgery (HSS) scores. IL-1β suppressed miR-30a expression by recruiting the activator protein (AP-1) transcription factor c-jun/c-fos to the miR-30a promoter. IL-1β-induced c-jun/c-fos expression regulated ADAMTS-5 expression and cartilage matrix degradation via miR-30a in human chondrocytes. These data indicate that the IL-1β/AP-1/miR-30a/ADAMTS-5 pathway contributes to IL-1β-induced cartilage matrix degradation in human OA chondrocytes. miR-30a may act as a pivotal regulator of cartilage homeostasis and a potential diagnostic and therapeutic target for OA.
  
  
  
  ADAMTS-5 was identified as a novel direct target of miR-30a. IL-1β suppresses miR-30a expression through activation of AP-1 (c-jun/c-fos). AP-1/miR-30a is essential for IL-1β-induced ADAMTS-5 upregulation in OA. Downregulation of miR-30a in OA is negatively correlated with ADAMTS-5 expression.
authors.affiliation: Department of Orthopaedics, General Hospital of Chinese People's Liberation Army, Beijing, 100853, China.
authors.forename: Quanbo
authors.initials: Q
authors.lastname: Ji
authors.affiliation: Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, 100850, China. miraclexxj@126.com.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Xu
authors.affiliation: Department of Orthopaedics, General Hospital of Chinese People's Liberation Army, Beijing, 100853, China.|Department of Orthopaedic Surgery, Royal Liverpool University Hospital, Prescot Street, Liverpool, UK.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Nuclear Medicine, Peking University First Hospital, Beijing, 100034, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Kang
authors.affiliation: Department of Traditional Chinese Medicine, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, China.
authors.forename: Yameng
authors.initials: Y
authors.lastname: Xu
authors.affiliation: Department of Science and Technology, Academy of Military Medical Sciences, Beijing, 100850, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, 100850, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, 100850, China.
authors.forename: Yingchun
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, 100850, China.
authors.forename: Tian
authors.initials: T
authors.lastname: Hong
authors.affiliation: Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, 100850, China.
authors.forename: Qinong
authors.initials: Q
authors.lastname: Ye
authors.affiliation: Department of Orthopaedics, General Hospital of Chinese People's Liberation Army, Beijing, 100853, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
mesh_terms: D020413:3' Untranslated Regions; D000071116:ADAMTS5 Protein / Q000235:genetics* / Q000378:metabolism; D000368:Aged; D019645:Arthroplasty, Replacement, Knee; D001483:Base Sequence; D001665:Binding Sites; D002358:Cartilage, Articular / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology; D019295:Computational Biology; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D053583:Interleukin-1beta / Q000235:genetics* / Q000378:metabolism; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D007719:Knee Joint / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D020370:Osteoarthritis, Knee / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D061251:Primary Cell Culture; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; C508585:IL1B protein, human; D053583:Interleukin-1beta; C546086:MIRN30b microRNA, human; D035683:MicroRNAs; D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1; D048031:JNK Mitogen-Activated Protein Kinases; D000071116:ADAMTS5 Protein; C121532:ADAMTS5 protein, human
keywords: ADAMTS-5; AP-1; IL-1β; Osteoarthritis; miR-30a