Engdahl Cecilia, Jochems Caroline, Windahl Sara H, Börjesson Anna E, Ohlsson Claes, Carlsten Hans, Lagerquist Marie K
Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
Arthritis Rheum. 2010 Feb;62(2):524-33. doi: 10.1002/art.25055.
The effects of estrogen may be exerted via the nuclear estrogen receptors (ERs) ERalpha or ERbeta or via the recently proposed transmembrane estrogen receptor G protein-coupled receptor 30 (GPR-30). The purpose of this study was to elucidate the ER specificity for the ameliorating effects of estrogen on arthritis and bone loss in a model of postmenopausal rheumatoid arthritis (RA).
Female DBA/1 mice underwent ovariectomy or sham operation, and type II collagen-induced arthritis was induced. Mice were treated subcutaneously 5 days/week with the specific agonists propylpyrazoletriol (PPT; for ERalpha), diarylpropionitrile (DPN; for ERbeta), G1 (for GPR-30), or with a physiologic dose of estradiol. Clinical arthritis scores were determined continuously. At termination of the study, bone mineral density (BMD) was analyzed, paws were collected for histologic assessment, serum was analyzed for cytokines and markers of bone and cartilage turnover, and bone marrow was subjected to fluorescence-activated cell sorting.
Treatment with PPT as well as estradiol dramatically decreased the frequency and severity of arthritis. Furthermore, estradiol and PPT treatment resulted in preservation of bone and cartilage, as demonstrated by increased BMD and decreased serum levels of bone resorption markers and cartilage degradation markers, whereas no effect was seen after DPN or G1 treatment.
In a well-established model of postmenopausal RA, ERalpha, but not ERbeta or GPR-30 signaling, was shown to ameliorate the disease and the associated development of osteoporosis. Since long-term treatment with estrogen has been associated with significant side effects, increased knowledge about the mechanisms behind the beneficial effects of estrogen is useful in the search for novel treatments of postmenopausal RA.
雌激素的作用可能通过核雌激素受体（ERs）α或β发挥，也可能通过最近提出的跨膜雌激素受体G蛋白偶联受体30（GPR-30）发挥。本研究的目的是在绝经后类风湿关节炎（RA）模型中阐明雌激素对关节炎和骨质流失改善作用的ER特异性。
雌性DBA/1小鼠接受卵巢切除术或假手术，并诱导II型胶原诱导的关节炎。小鼠每周皮下注射5天，分别给予特异性激动剂丙基吡唑三醇（PPT；针对ERα）、二芳基丙腈（DPN；针对ERβ）、G1（针对GPR-30），或生理剂量的雌二醇。连续测定临床关节炎评分。在研究结束时，分析骨密度（BMD），收集爪子进行组织学评估，分析血清中的细胞因子以及骨和软骨周转标志物，并对骨髓进行荧光激活细胞分选。
PPT以及雌二醇治疗显著降低了关节炎的频率和严重程度。此外，雌二醇和PPT治疗导致骨和软骨得以保留，表现为BMD增加以及骨吸收标志物和软骨降解标志物的血清水平降低，而DPN或G1治疗后未见效果。
在一个成熟的绝经后RA模型中，已证明是ERα而非ERβ或GPR-30信号传导改善了疾病及相关的骨质疏松症发展。由于长期使用雌激素与显著的副作用相关，增加对雌激素有益作用背后机制的了解有助于寻找绝经后RA的新治疗方法。
