Role of raloxifene as a potent inhibitor of experimental postmenopausal polyarthritis and osteoporosis
Role of raloxifene as a potent inhibitor of experimental postmenopausal polyarthritis and osteoporosis
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DOI：
10.1002/art.22873
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发表时间：
2007-10-01
影响因子：
--
通讯作者：
Carlsten, Hans
中科院分区：
文献类型：
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作者：
Jochems, Caroline;Islander, Ulrika;Carlsten, Hans
目标。在绝经后类风湿关节炎（RA）中，雌激素缺乏和炎症性疾病都有助于广泛性骨质疏松症的发展。激素替代疗法（HRT）与雌二醇保持骨密度（BMD）和改善关节炎，但长期治疗不再是一种选择，因为显著的副作用。因此，我们使用了人类RA的小鼠模型来验证选择性雌激素受体调节剂（SERM），雷洛昔芬类似物LY117018，可能有益于治疗关节炎和骨质疏松症的假设。雌性DBA/1小鼠去卵巢，胶原免疫诱导关节炎。小鼠注射雷洛昔芬、雌二醇或对照物，预防或治疗，随后连续评估临床关节炎评分。终止时，用周围定量计算机断层扫描分析骨密度。收集爪子进行组织学检查，分析血清中细胞因子和骨、软骨转换标志物。实时聚合酶链反应检测细胞因子信使RNA （mRNA）水平。雷洛昔芬治疗显著降低了关节炎的发生频率和严重程度。与对照组相比，雷洛昔芬暴露小鼠的骨密度增加，血清软骨寡聚基质蛋白水平降低，可见骨骼和软骨得到有效保存。雷洛昔芬治疗的关节炎小鼠脾脏细胞中肿瘤坏死因子a和RANKL mRNA水平降低，表明该血清具有免疫抑制作用。在一个成熟的绝经后RA模型中，雷洛昔芬类似物LY117018在预防和治疗方案中都能有效抑制关节炎的进展和骨质疏松症的相关发展。由于长期激素替代疗法与显著的副作用相关，雷洛昔芬可能是绝经后RA的有用辅助治疗。
Objective. In postmenopausal rheumatoid arthritis (RA), both estrogen deficiency and the inflammatory disease contribute to the development of generalized osteoporosis. Hormone replacement therapy (HRT) with estradiol preserves bone mineral density (BMD) and ameliorates arthritis, but long-term therapy is no longer an option due to significant side effects. We therefore used a mouse model of human RA to test the hypothesis that a selective estrogen receptor modulator (SERM), the raloxifene analog LY117018, could be beneficial in the treatment of both arthritis and,osteoporosis.Methods. Female DBA/1 mice were ovariectomized and arthritis was induced with collagen immunization. Mice received an injection of raloxifene, estradiol, or vehicle control, administered prophylactically or therapeutically, and thereafter the clinical arthritis score was evaluated continuously. At termination, BMD was analyzed with peripheral quantitative computed tomography. Paws were collected for histology, and sera were analyzed for cytokines and markers of bone and cartilage turnover. Levels of cytokine messenger RNA (mRNA) were investigated with real-time polymerase chain reaction.Results. Treatment with raloxifene dramatically decreased the frequency and severity of arthritis. Effective preservation of bone and cartilage was seen in raloxifene-exposed mice, as demonstrated by increased BMD and decreased serum levels of cartilage oligomeric matrix protein in the raloxifene-treated mice compared with controls. Decreased levels of mRNA for both tumor necrosis factor a and RANKL in spleen cells from raloxifene-treated arthritic mice indicated an immunosuppressive action of this SERM.Conclusion. In a well-established model of postmenopausal RA, the raloxifene analog LY117018 potently inhibits the progression of arthritis and the associated development of osteoporosis, both in a prophylactic and in a therapeutic regimen. Since long-term HRT has been associated with significant side effects, raloxifene may be a useful adjuvant treatment for postmenopausal RA.