title: miR-105/Runx2 axis mediates FGF2-induced ADAMTS expression in osteoarthritis cartilage.
abstract: Fibroblast growth factor 2 (FGF2) plays an important role in the development of osteoarthritis (OA) through the regulation of cartilage degradation. However, the molecular mechanism underlying FGF2-induced OA is poorly characterized. MicroRNAs (miRNAs) maintain cartilage homeostasis. To examine whether FGF2 regulates OA through the modulation of miRNA, we screened potential miRNA molecules that could be regulated through FGF2 using microarray analysis. The results showed that microRNA-105 (miR-105) was significantly downregulated in chondrocytes stimulated with FGF2. Runt-related transcription factor 2 (Runx2), a key transcription factor involved in OA, has been identified as a novel potential target of miR-105. FGF2 suppressed miR-105 expression through the recruitment of the subunit of the nuclear factor kappa B transcription complex p65 to the miR-105 promoter. The knockdown of Runx2 mimicked the effect of miR-105 and abolished the ability of miR-105 to regulate the expression of a disintegrin-like and metalloproteinase with thrombospondin 4 (ADAMTS4), ADAMTS5, ADAMTS7 and ADAMTS12, both of which are responsible for the degradation of collagen 2A1 (COL2A1) and aggrecan (ACAN). miR-105 is also required for FGF2/p65-induced Runx2 activation and ADAMTS expression. Moreover, miR-105 expression was downregulated in OA patients and inversely correlated with the expression of Runx2, ADAMTS7 and ADAMTS12, which were upregulated in OA patients. These data highlight that the FGF2/p65/miR-105/Runx2/ADAMTS axis might play an important role in OA pathogenesis and that miR-105 might be a potential diagnostic target and useful strategy for OA treatment.
  
  
  
  Runx2 was identified as a novel direct target of miR-105. FGF2 inhibits miR-105 transcription through recruitment of p65 to miR-105 promoter. p65/miR-105 is essential for FGF2-mediated Runx2 and ADAMTS upregulation. miR-105 is downregulated in OA and inversely correlated with Runx2 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.
authors.forename: Xiaojie
authors.initials: X
authors.lastname: Xu
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 Oncology, General Hospital of Chinese People's Liberation Army, Beijing, 100853, China.
authors.forename: Zhongyi
authors.initials: Z
authors.lastname: Fan
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 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: Jing
authors.initials: J
authors.lastname: Guo
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 Orthopaedics, General Hospital of Chinese People's Liberation Army, Beijing, 100853, China.
authors.forename: Zhongli
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Orthopaedics, General Hospital of Chinese People's Liberation Army, Beijing, 100853, China. 301zhangqiang@gmail.com.|Department of Orthopaedic Surgery, Royal Liverpool University Hospital, Prescot Street, Liverpool, UK. 301zhangqiang@gmail.com.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Medical Molecular Biology, Beijing Institute of Biotechnology, Beijing, 100850, China. yeqn66@yahoo.com.
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. yanwang301@126.com.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
mesh_terms: D000071096:ADAMTS Proteins / Q000235:genetics* / Q000378:metabolism; D000071118:ADAMTS7 Protein / Q000235:genetics / Q000378:metabolism; D000368:Aged; D053674:Aggrecans / Q000235:genetics / Q000378:metabolism; D019645:Arthroplasty, Replacement, Knee; D001483:Base Sequence; D002358:Cartilage, Articular / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D019902:Chondrocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D024043:Collagen Type II / Q000235:genetics / Q000378:metabolism; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics* / Q000378:metabolism; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000494:pharmacology*; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D046228:Microarray Analysis; D008875:Middle Aged; D020370:Osteoarthritis, Knee / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D061251:Primary Cell Culture; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism
chemical_list: C508319:ACAN protein, human; D053674:Aggrecans; C499177:COL2A1 protein, human; D024043:Collagen Type II; D050659:Core Binding Factor Alpha 1 Subunit; C588223:MIRN105 microRNA, human; D035683:MicroRNAs; C498143:RELA protein, human; C493709:RUNX2 protein, human; D051996:Transcription Factor RelA; D016222:Fibroblast Growth Factor 2; D000071096:ADAMTS Proteins; C496252:ADAMTS12 protein, human; D000071118:ADAMTS7 Protein; C121534:ADAMTS7 protein, human
keywords: ADAMTS; FGF2; Osteoarthritis; RUNX2; miR-105
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