Estrone/17β-Estradiol Conversion to, and Tumor Necrosis Factor Inhibition by, Estrogen Metabolites in Synovial Cells of Patients With Rheumatoid Arthritis and Patients With Osteoarthritis

Objective. The role of estrogens in rheumatoid arthritis (RA) is debated since both proinflammatory and antiinflammatory effects have been reported. Important evidence of the dual role of estrogens is conversion to various proinflammatory or anti inflammatory metabolites. This study was undertaken to examine the downstream conversion of estrogens in synovial cells from patients with RA or osteoarthritis (OA). Methods. We studied serum levels of estrone, estrone sulfate, and estrone sulfate membrane transporters, intracellular interconversion of estrone and 17 beta-estradiol, and conversion of estrone/17 beta-estradiol to various estrogen metabolites in RA and OA synovial cells. The effect of estrogen metabolites on tumor necrosis factor (TNF) secretion was also studied in RA and OA synovial cells. Results. Serum levels of estrone sulfate were similar in healthy controls and RA patients. Estrone sulfate transporters were present in synovial tissue. Interconversion of estrone and 17 beta-estradiol and the expression of converting enzymes of the cytochrome P450 family were similar in RA and OA cells. Using estrone and 17 beta-estradiol as substrates, RA and OA synovial cells produced 16 alpha-, 4-, and 2-hydroxylated estrogens and their 4- and 2-methylation products. The levels of 16 alpha-hydroxylated estrone/17 beta-estradiol (16 alpha OH-estrone/16 alpha OH-17 beta-estradiol) were higher than the levels of all other estrogen metabolites. RA synovial cells produced more 16 alpha OH-estrone than did OA synovial cells. Importantly, the 16 alpha OH estrogens did not inhibit TNF secretion, whereas all other estrogen metabolites had marked inhibitory effects. Conclusion. Our findings indicate that precursor estrogens are converted to proinflammatory metabolites, particularly in RA synovial cells. RA synovial cells mainly produce the proproliferative 16 alpha OH-estrone, which, in addition to 16 alpha OH-17 beta-estradiol, is one of the only 2 estrogens studied that does not inhibit TNF secretion. A preponderance of 16 alpha-hydroxylated estrogens is an unfavorable sign in synovial inflammation.