Estrogen and progesterone regulation of human fibroblast-like synoviocyte function in vitro: Implications in rheumatoid arthritis

Objective. Despite increasing evidence regarding the significance of sex ho rmones in rheumatoid arthritis (RA), their etiopathological role and potent ial longterm effect on joint destruction remain unclear. We hypothesized th at estrogen receptors (ER-alpha) are present in fibroblast-like synsviocyte s, and 17 beta-estradiol can modulate the production and activity of matrix degrading enzymes produced by these cells. Thus, depending on the endocrin e balance, fibroblast-like synoviocyte activity call be suppressed or enhan ced, leading to amelioration or exacerbation of the disease process, respec tively. Methods, By utilizing an in vitro cartilage invasion model, in combination with the molecular analyses of hormone receptors, matrix metalloproteinases (MMP) and their respective inhibitors, we investigated the effect of hormo nes (i.e., estrogen and progesterone) on fibroblast-like synoviocyte phenot ypic changes, with particular emphasis on their functional interactions wit h cartilage. Results. Our studies reveal the presence of functional ER-alpha in fibrobla st-like synoviocytes. The findings indicate that estrogen exerts a stimulat ory effect, while progesterone has an inhibitory effect on the expression o f MMP, their tissue inhibitors (TIMP), and enzymatic activity of MMP produc ed by these cells. Furthermore, transfection of fibroblast-like synoviocyte s with the ER-alpha gene resulted in the increased degradation and invasion of cartilage. Conclusion. We identified the presence of functional ER-alpha in fibroblast -like synoviocytes. This renders fibroblast-like synoviocytes as target cel ls for hormonal regulation. The regulatory effect of estrogen is partly tar geted to the MMP and their respective inhibitors associated with fibroblast -like synoviocytes. Such studies provide a link between hormonal status and disease activity in RA and open new venues for future therapeutic interven tion to combat this debilitating disease.