Sex steroid receptors in rheumatoid arthritis

Rheumatoid arthritis (RA) is a disease characterized primarily by chronic inflammatory synovitis and is well-known to be associated with significant sex differences in its prevalence and clinical features. Sex steroids have been proposed to be involved in the pathogenesis of RA, but details pertaining to the expression of sex steroid receptors in RA synovial tissue have yet to be fully characterized. In the present study, we examined oestrogen receptor (ER) α, ERβ, progesterone receptor (PR) and androgen receptor (AR) mRNA expression using real-time reverse transcriptase–PCR (RT-PCR) in eight female RA synovial tissues and six female synovial tissues without inflammation, and determined immunolocalization of ERα, ERβ, PR-A, PR-B and AR using immunohistochemistry in synovial tissues obtained from 22 RA patients. Real-time RT-PCR analysis demonstrated the expression of ER, PR and AR mRNAs in both RA and non-inflamed synovial tissues. Relative abundance of ER mRNAs was significantly higher in RA synovial tissue than non-inflamed synovial tissue (P<0.05). In addition, the relative ERα/ERβ mRNA expression ratio was significantly lower in RA than non-inflamed synovial tissue (RA, 2.34±1.60; and non-inflamed, 20.7±19.1; P<0.05). There were no significant differences in relative abundance of PR mRNA. Relative abundance of AR mRNA was significantly lower in RA (P<0.05). Immunoreactivity for ERα, ERβ, PR-B and AR was detected in the lining cells, inflammatory cells and fibroblasts in all the patients examined. The labelling indices for ERβ and PR-B were more abundant in both lining cells (ERβ, 54.2±12.2%; PR-B, 73.6±18.9%) and inflammatory cells (ERβ, 74.6±16.2%; PR-B, 75.9±16.1%) than in fibroblasts (ERβ, 36.5±15.6%; PR-B, 49.4±18.0%). Labelling indices for ERα and AR were significantly higher in lining cells (ERα, 14.4±8.6%; AR, 31.2±11.3%) and fibroblasts (ERα, 12.1±7.5%; AR, 20.1±9.6%) than those in inflammatory cells (ERα, 5.7±3.3%; AR, 9.2±4.4%). There were significant differences (P<0.05) in the labelling indices for ERα, ERβ and PR-B between men and women under 50 years of age in fibroblasts of RA synovial tissues. These results indicate that sex steroid receptors are present in RA and non-inflamed synovial tissues, including inflammatory cells in RA, and suggest that sex steroids may play important roles in the regulation of inflammation of RA synovial tissue.