雌激素对胶原诱导关节炎动物模型发病过程的作用

Effects of estrogen on disease development in collagen-induced arthritis animal models

目的研究雌激素对胶原诱导关节炎(CIA)发病过程的影响以及对肽基精酰胺脱亚胺基酶4(PADI4)和TXNDC5表达的影响。方法雄性Lewis大鼠29只随机分成4组:正常对照组(H组,n=6)、CIA模型组(C组,n=8)、雌激素干预组(T组,n=8)和雌激素组(E组,n=7)。皮下注射牛Ⅱ型胶原(CⅡ)建立CIA模型,其间进行雌激素干预。ELISA法检测血清中肿瘤坏死因子α(TNFα)、白介素-1β(IL-1β)和血管内皮生长因子(VEGF)的含量;免疫组织化学法、Western-blot法和real-time PCR法检测滑膜中PADI4和TXNDC5的表达。结果与C组相比,T组的关节炎发病时间约延缓6d(P=0.045),炎症程度和发病率无显著差异;TNFα和IL-1β的含量无明显改变,VEGF含量明显升高(P=0.023);T组滑膜组织异常增殖并伴毛细血管增生,PADI4主要表达于滑膜衬里及侵润的炎性细胞,TXNDC5主要分布于滑膜衬里及毛细血管的内皮细胞。雌激素明显刺激CIA滑膜中TXNDC5的表达(P<0.05),但对PADI4的表达无显著影响。结论雌激素虽然能延缓关节炎的发病时间,但可能通过上调TXNDC5的表达,刺激类风湿关节炎(RA)滑膜毛细血管增生。

Objective To investigate the effects of estrogen on disease development and expressions of peptidylarginine deiminase 4（PADI4） and thioredoxin domain containing protein 5（TXNDC5） in collagen induced arthritis（CIA） models.Methods Twenty-nine male Lewis rats were randomly divided into four groups： the healthy control group（group H,n=6）,the CIA group（group C,n=8）,the CIA group treated with estrogen（group T,n=8） and the estrogen group（group E,n=7）.CIA was induced subcutaneously with bovine type Ⅱcollagen（CⅡ） and estrogen treatment was operated during CⅡsensitization.ELISA was used to measure the levels of TNFα,IL-1β and VEGF in serum samples.Immunohistochemisty,Western-blot and real-time PCR were applied to detect expressions of PADI4 and TXNDC5 in synovial membranes.Results Compared with group C,the onset of CIA was significantly delayed for 6 days（P=0.045） with no effects on inflammatory severity and incidence rates of the disease in group T;the serum levels of TNFαand IL-1β were not evidently altered,but the level of VEGF was considerably increased（P=0.023）.Synovial tissues in group T showed more hyperplasia with angiogenesis,in which PADI4 was mainly expressed in the lining and infiltrated inflammatory cells of synovium and TXNDC5 was mainly presented in the lining of synovium and endotheliocytes of capillaries.Estrogen pronouncedly stimulates expression of TXNDC5（P0.05） rather than expression of PADI4.Conclusion Although estrogen can delay the onset of arthritis,it may stimulate angiogenesis in rheumatoid arthritis synovium via the up-regulation of TXNDC5.