Estrogen inhibits apoptosis and promotes CC motif chemokine ligand 13 expression on synovial fibroblasts in rheumatoid arthritis

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 (E₂). The effects of E₂ against cellular activation and apoptosis were evaluated. To identify the disease-related genes altered by E₂ treatment, the changes in the gene expression of the cells stimulated with and without E₂ were evaluated using a microarray analysis.

Results: We found that E₂-mediated cellular activation signaling through extracellular signal-regulated kinase (ERK)-1/2. E₂ 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 E₂ profoundly upregulated CC motif chemokine ligand 13 (CCL13) gene expression.

Conclusions: E₂ could mediate cellular activation signaling through ERK-1/2 on the synovial fibroblasts. The present data suggest that E₂ 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.