Schmidt Martin, Hartung Regina, Capellino Silvia, Cutolo Maurizio, Pfeifer-Leeg Antje, Straub Rainer H
University Hospital Jena, Jena, Germany.
Arthritis Rheum. 2009 Oct;60(10):2913-22. doi: 10.1002/art.24859.
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 antiinflammatory metabolites. This study was undertaken to examine the downstream conversion of estrogens in synovial cells from patients with RA or osteoarthritis (OA).
We studied serum levels of estrone, estrone sulfate, and estrone sulfate membrane transporters, intracellular interconversion of estrone and 17beta-estradiol, and conversion of estrone/17beta-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.
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 17beta-estradiol and the expression of converting enzymes of the cytochrome P450 family were similar in RA and OA cells. Using estrone and 17beta-estradiol as substrates, RA and OA synovial cells produced 16alpha-, 4-, and 2-hydroxylated estrogens and their 4- and 2-methylation products. The levels of 16alpha-hydroxylated estrone/17beta-estradiol (16alphaOH-estrone/16alphaOH-17beta-estradiol) were higher than the levels of all other estrogen metabolites. RA synovial cells produced more 16alphaOH-estrone than did OA synovial cells. Importantly, the 16alphaOH estrogens did not inhibit TNF secretion, whereas all other estrogen metabolites had marked inhibitory effects.
Our findings indicate that precursor estrogens are converted to proinflammatory metabolites, particularly in RA synovial cells. RA synovial cells mainly produce the proproliferative 16alphaOH-estrone, which, in addition to 16alphaOH-17beta-estradiol, is one of the only 2 estrogens studied that does not inhibit TNF secretion. A preponderance of 16alpha-hydroxylated estrogens is an unfavorable sign in synovial inflammation.
雌激素在类风湿关节炎（RA）中的作用存在争议，因为有报道称其具有促炎和抗炎双重作用。雌激素双重作用的重要证据是其转化为各种促炎或抗炎代谢产物。本研究旨在检测RA或骨关节炎（OA）患者滑膜细胞中雌激素的下游转化情况。
我们研究了血清中雌酮、硫酸雌酮及其膜转运蛋白水平，RA和OA滑膜细胞中雌酮与17β-雌二醇的细胞内相互转化，以及雌酮/17β-雌二醇向各种雌激素代谢产物的转化。还研究了雌激素代谢产物对RA和OA滑膜细胞中肿瘤坏死因子（TNF）分泌的影响。
健康对照者和RA患者的血清硫酸雌酮水平相似。滑膜组织中存在硫酸雌酮转运蛋白。RA和OA细胞中雌酮与17β-雌二醇的相互转化以及细胞色素P450家族转化酶的表达相似。以雌酮和17β-雌二醇为底物，RA和OA滑膜细胞产生了16α-、4-和2-羟基化雌激素及其4-和2-甲基化产物。16α-羟基化雌酮/17β-雌二醇（16αOH-雌酮/16αOH-17β-雌二醇）的水平高于所有其他雌激素代谢产物。RA滑膜细胞产生的16αOH-雌酮比OA滑膜细胞多。重要的是，16αOH雌激素不抑制TNF分泌，而所有其他雌激素代谢产物均有显著抑制作用。
我们的研究结果表明，前体雌激素可转化为促炎代谢产物，尤其是在RA滑膜细胞中。RA滑膜细胞主要产生促增殖的16αOH-雌酮，它与16αOH-17β-雌二醇一样，是所研究的仅有的两种不抑制TNF分泌的雌激素之一。16α-羟基化雌激素占优势在滑膜炎症中是一个不利迹象。
