title: Estrogen inhibits apoptosis and promotes CC motif chemokine ligand 13 expression on synovial fibroblasts in rheumatoid arthritis.
abstract: OBJECTIVE
  Female patients have a higher prevalence of rheumatoid arthritis (RA) than male patients, suggesting that female sex hormones contribute to the disease pathogenesis. We herein report the findings of our study, which was conducted to clarify the role of estrogen in the pathogenesis of RA.
  
  
  METHODS
  Cultured human synovial fibroblasts from a patient with RA were treated with 17β-estradiol (E(2)). The effects of E(2) against cellular activation and apoptosis were evaluated. To identify the disease-related genes altered by E(2) treatment, the changes in the gene expression of the cells stimulated with and without E(2) were evaluated using a microarray analysis.
  
  
  RESULTS
  We found that E(2)-mediated cellular activation signaling through extracellular signal-regulated kinase (ERK)-1/2. E(2) possessed a suppressive effect for apoptosis and a promotive effect for tumor necrosis factor (TNF)-α-induced matrix metalloproteinase (MMP)-3 production on the synovial fibroblasts. A microarray analysis revealed that E(2) profoundly upregulated CC motif chemokine ligand 13 (CCL13) gene expression.
  
  
  CONCLUSIONS
  E(2) could mediate cellular activation signaling through ERK-1/2 on the synovial fibroblasts. The present data suggest that E(2) has adverse effects on the pathogenesis of RA as a result of unregulated cell death, increased TNF-α-induced MMP-3 production, and CCL13 overproduction, subsequently resulting in the disease progression of RA.
authors.affiliation: Institute for Environment and Gender-Specific Medicine, Juntendo University, Graduate School of Medicine, Chiba, Japan.
authors.forename: Ayako
authors.initials: A
authors.lastname: Yamaguchi
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Nozawa
authors.forename: Maki
authors.initials: M
authors.lastname: Fujishiro
authors.forename: Mikiko
authors.initials: M
authors.lastname: Kawasaki
authors.forename: Kenji
authors.initials: K
authors.lastname: Takamori
authors.forename: Hideoki
authors.initials: H
authors.lastname: Ogawa
authors.forename: Iwao
authors.initials: I
authors.lastname: Sekigawa
authors.forename: Yoshinari
authors.initials: Y
authors.lastname: Takasaki
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D004958:Estradiol / Q000009:adverse effects* / Q000494:pharmacology; D004967:Estrogens / Q000009:adverse effects* / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D019278:Matrix Metalloproteinase 3 / Q000096:biosynthesis; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D018945:Monocyte Chemoattractant Proteins / Q000096:biosynthesis*; D020411:Oligonucleotide Array Sequence Analysis; D013583:Synovial Membrane / Q000378:metabolism* / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: C099677:CCL13 protein, human; D004967:Estrogens; D018945:Monocyte Chemoattractant Proteins; D014409:Tumor Necrosis Factor-alpha; D004958:Estradiol; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C511768:MMP3 protein, human; D019278:Matrix Metalloproteinase 3