Jochems Caroline, Islander Ulrika, Kallkopf Anna, Lagerquist Marie, Ohlsson Claes, Carlsten Hans
Sahlgrenska Academy at Göteborg University, Göteborg, Sweden.
Arthritis Rheum. 2007 Oct;56(10):3261-70. doi: 10.1002/art.22873.
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.
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.
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 alpha and RANKL in spleen cells from raloxifene-treated arthritic mice indicated an immunosuppressive action of this SERM.
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.
在绝经后类风湿关节炎（RA）中，雌激素缺乏和炎症性疾病均会导致全身性骨质疏松症的发生。雌二醇激素替代疗法（HRT）可维持骨矿物质密度（BMD）并改善关节炎症状，但由于存在显著副作用，长期治疗已不再是一种选择。因此，我们使用人类RA小鼠模型来检验以下假设：一种选择性雌激素受体调节剂（SERM），雷洛昔芬类似物LY117018，可能对关节炎和骨质疏松症的治疗均有益。
对雌性DBA/1小鼠进行卵巢切除，并通过胶原蛋白免疫诱导关节炎。小鼠预防性或治疗性注射雷洛昔芬、雌二醇或载体对照，此后持续评估临床关节炎评分。处死时，用外周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，并分析血清中的细胞因子以及骨和软骨周转标志物。用实时聚合酶链反应研究细胞因子信使核糖核酸（mRNA）水平。
雷洛昔芬治疗显著降低了关节炎的频率和严重程度。与对照组相比，雷洛昔芬处理的小鼠骨密度增加，血清软骨寡聚基质蛋白水平降低，表明雷洛昔芬处理的小鼠的骨和软骨得到有效保存。雷洛昔芬处理的关节炎小鼠脾细胞中肿瘤坏死因子α和核因子κB受体活化因子配体（RANKL）的mRNA水平降低，表明该SERM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在预防性和治疗性方案中均能有效抑制关节炎的进展以及相关骨质疏松症的发展。由于长期HRT与显著副作用相关，雷洛昔芬可能是绝经后RA的一种有用辅助治疗药物。
