title: Histone Methylation and STAT-3 Differentially Regulate Interleukin-6-Induced Matrix Metalloproteinase Gene Activation in Rheumatoid Arthritis Synovial Fibroblasts.
abstract: Synovial fibroblasts (SFs) produce matrix-degrading enzymes that cause joint destruction in rheumatoid arthritis (RA). Epigenetic mechanisms play a pivotal role in autoimmune diseases. This study was undertaken to elucidate the epigenetic mechanism that regulates the transcription of matrix metalloproteinases (MMPs) in RASFs.
  
  
  
  MMP gene expression and histone methylation profiles in the MMP promoters were examined in RASFs. The effect of WD repeat domain 5 (WDR5) silencing on histone methylation and MMP gene expression in RASFs was analyzed. MMP gene expression, surface expression of the interleukin-6 (IL-6) receptor, phosphorylation of STAT-3, and binding of STAT-3 in the MMP promoters were investigated in RASFs stimulated with IL-6.
  
  
  
  The MMP-1, MMP-3, MMP-9, and MMP-13 genes were actively transcribed in RASFs. Correspondingly, the level of histone H3 trimethylated at lysine 4 (H3K4me3) was elevated, whereas that of H3K27me3 was suppressed in the MMP promoters in RASFs. The decrease in H3K4me3 via WDR5 small interfering RNA reduced the levels of messenger RNA for MMP-1, MMP-3, MMP-9, and MMP-13 in RASFs. Interestingly, IL-6 signaling significantly increased the expression of MMP-1, MMP-3, and MMP-13, but not MMP-9, in RASFs. Although the IL-6 signaling pathway was similarly active in RASFs and osteoarthritis SFs, STAT-3 bound to the MMP-1, MMP-3, and MMP-13 promoters, but not the MMP-9 promoter, after IL-6 stimulation in RASFs.
  
  
  
  Our findings indicate that histone methylation and STAT-3 regulate spontaneous and IL-6-induced MMP gene activation in RASFs. The combination of chromatin structure and transcription factors may regulate distinct arthritogenic properties of RASFs.
authors.affiliation: Saitama Medical University, Saitama, Japan.
authors.forename: Yasuto
authors.initials: Y
authors.lastname: Araki
authors.affiliation: Saitama Medical University, Saitama, Japan.
authors.forename: Takuma
authors.initials: T
authors.lastname: Tsuzuki Wada
authors.affiliation: Saitama Medical University, Saitama, Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Aizaki
authors.affiliation: Saitama Medical University, Saitama, Japan.
authors.forename: Kojiro
authors.initials: K
authors.lastname: Sato
authors.affiliation: Saitama Medical University, Saitama, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yokota
authors.affiliation: Saitama Medical University, Saitama, Japan.
authors.forename: Kenta
authors.initials: K
authors.lastname: Fujimoto
authors.affiliation: Saitama Medical University, Saitama, Japan.
authors.forename: Yoon-Taek
authors.initials: YT
authors.lastname: Kim
authors.affiliation: Saitama Medical University, Saitama, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Oda
authors.affiliation: Saitama Medical University, Saitama, Japan.
authors.forename: Riki
authors.initials: R
authors.lastname: Kurokawa
authors.affiliation: Saitama Medical University, Saitama, Japan.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Mimura
mesh_terms: D001172:Arthritis, Rheumatoid / Q000235:genetics* / Q000276:immunology; D015153:Blotting, Western; D016022:Case-Control Studies; D047369:Chromatin Immunoprecipitation; D005347:Fibroblasts / Q000276:immunology / Q000378:metabolism*; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology*; D042421:Histone Code; D006657:Histones / Q000378:metabolism*; D006801:Humans; D015850:Interleukin-6 / Q000276:immunology*; D020781:Matrix Metalloproteinase 1 / Q000235:genetics / Q000276:immunology; D053509:Matrix Metalloproteinase 13 / Q000235:genetics / Q000276:immunology; D019278:Matrix Metalloproteinase 3 / Q000235:genetics / Q000276:immunology; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000276:immunology; D020782:Matrix Metalloproteinases / Q000235:genetics* / Q000276:immunology; D008745:Methylation; D020370:Osteoarthritis, Knee / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000276:immunology*; D013583:Synovial Membrane / Q000166:cytology*; D015533:Transcriptional Activation
chemical_list: D006657:Histones; C508600:IL6 protein, human; D015850:Interleukin-6; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C507079:MMP13 protein, human; D053509:Matrix Metalloproteinase 13; D020782:Matrix Metalloproteinases; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; C522360:MMP1 protein, human; D020781:Matrix Metalloproteinase 1