Effects of oestradiol and raloxifene on the induction and effector phases of experimental postmenopausal arthritis and secondary osteoporosis
Effects of oestradiol and raloxifene on the induction and effector phases of experimental postmenopausal arthritis and secondary osteoporosis
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DOI：
10.1111/j.1365-2249.2011.04397.x
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发表时间：
2011-07-01
影响因子：
4.6
通讯作者：
Carlsten, H.
中科院分区：
文献类型：
--
作者：
Jochems, C.;Islander, U.;Carlsten, H.
雌二醇和选择性雌激素受体调节剂（SERM）雷洛昔芬已被证明可以改善大鼠和小鼠的胶原诱导性关节炎（CIA）。一个目的是研究雷洛昔芬是否在关节炎的诱导期或效应期发挥其抗关节炎和抗关节炎作用。第二个目的是分析雷洛昔芬是否激活雌激素反应元件（ERE），以产生其免疫调节作用。在切除卵巢的DBA/1小鼠中诱导CIA或胶原抗体诱导的关节炎（CAIA）。CIA用于评估诱导期间的治疗，CAIA用于关节炎和骨质疏松症发展的效应期。雷洛昔芬、雌二醇或溶媒给药，每周5天。连续评估临床疾病。用外周定量计算机断层扫描分析骨髓密度（BMD），收集爪进行组织学检查，并分析血清中的骨和软骨转换标志物和促炎细胞因子。用胶原蛋白（CII）免疫转基因荧光素酶（Luc）-ERE小鼠，10天后在处死前注射雷洛昔芬、雌二醇或溶媒一次。分析脾脏的荧光素酶活性以测量ERE活化。在CIA的诱导阶段用雌二醇或雷洛昔芬治疗未能影响关节炎。雷洛昔芬并不妨碍CAIA的疾病活动，而雌二醇延迟发病和改善严重程度。雷洛昔芬和雌二醇均能保护CAIA患者的BMD。CII免疫增加了雌二醇诱导的脾ERE激活，雷洛昔芬激活ERE的强度约为雌二醇的25%。需要进一步的实验来阐明这一发现背后的确切机制。
P>Oestradiol and the selective oestrogen receptor modulator (SERM) raloxifene have been shown to ameliorate collagen-induced arthritis (CIA) in rats and in mice. One aim was to investigate if raloxifene exerts its anti-arthritic and anti-osteoporotic effects during the induction or effector phase of arthritis. A second aim was to analyse if raloxifene activates the oestrogen response element (ERE) to produce its immune-modulator effects. CIA or collagen-antibody-induced arthritis (CAIA) was induced in ovariectomized DBA/1-mice. CIA was used for evaluation of treatment during the induction, and CAIA for the effector phase of arthritis and osteoporosis development. Raloxifene, oestradiol or vehicle was administered 5 days/week. The clinical disease was evaluated continuously. Bone marrow density (BMD) was analysed with peripheral quantitative computer tomography, paws were collected for histological examination, and sera were analysed for markers of bone and cartilage turnover and proinflammatory cytokines. Transgenic luciferase (Luc)-ERE mice were immunized with collagen (CII), and after 10 days injected once with raloxifene, oestradiol or vehicle before termination. Spleens were analysed for luciferase activity to measure ERE activation. Treatment with oestradiol or raloxifene during the induction phase of CIA failed to affect arthritis. Raloxifene did not hamper disease activity in CAIA, whereas oestradiol delayed the onset and ameliorated the severity. Both raloxifene and oestradiol preserved BMD in CAIA. CII-immunization increased the oestradiol-induced ERE activation in spleen, and raloxifene activated the ERE at about 25% the intensity of oestradiol. Further experiments are needed to elucidate the exact mechanisms behind this finding.