^(99)Tc-亚甲基二膦酸盐对胶原诱导性关节炎大鼠的治疗作用及其对滑膜MMP-3和TIMP-1的影响

Study of the treatment of ^(99)Tc-methylene diphosphonate on type Ⅱ collagen induced arthritis in rats and its effect on the synovial matrix metalloproteinase-3 and tissue inhibitor of matrix metalloproteinase-1

目的观察^(99)Tc-亚甲基二膦酸盐(^(99)Tc-MDP)对Ⅱ型胶原诱导性关节炎(CIA)大鼠的治疗作用及其对滑膜基质金属蛋白酶-3(MMP-3)、基质金属蛋白酶组织抑制物-1(TIMP-1)的影响,探讨^(99)Tc-MDP治疗类风湿关节炎(RA)的机制。方法建立CIA大鼠关节炎模型,分为正常对照组、模型对照组、^(99)Tc-MDP组和甲氨蝶呤组。采用关节炎指数评分法评价其关节的炎症程度；观察关节病理组织形态学变化；反转录-聚合酶链反应(RT-PCR)法检测滑膜MMP-3和TIMP-1 mRNA水平。结果①模型组、甲氨蝶呤组、^(99)Tc-MDP组大鼠随着免疫时间延长关节炎指数(Al)评分增加。②模型组关节组织学评分均高于甲氨蝶呤组和^(99)Tc-MDP组(P＜0．05)；软骨破坏和骨质破坏评分,^(99)Tc-MDP组低于甲氨蝶呤组(P＜0．05)。③模型组、甲氨蝶呤组、^(99)Tc-MDP组MMP-3 mRNA水平显著高于正常组(P＜0．01)；模型组高于^(99)Tc-MDP组(P＜0．05)。各组滑膜TIMP-1 mRNA水平差异无统计学意义(P＞0．05)。结论^(99)Tc-MDP明显减轻CIA大鼠的关节炎症状,延缓关节破坏的进展；^(99)Tc-MDP降低滑膜MMP-3 mRNA水平,可能是其治疗RA的机制之一；在延缓CIA大鼠软骨和骨质破坏的病理学改变及降低滑膜MMP-3 mRNA水平,其近期疗效优于甲氨蝶呤。

Objective To observe the treatment of ^99Tc-MDP on type Ⅱ collagen induced arthritis （CIA） in rat, and the effect on the expression of synovial MMP-3 and TIMP-1 mRNA. To explore the mech anisms of the ^99Tc-MDP in the treatment of rheumatoid arthritis. Methods The rats in which CIA （n=24） were divided into three group： the control group （n=8）, ^99Tc-MDP group （n=8） and Methotrexate group （n=8）. Arthritis were evaluated by arthritis index and histopathological index and the expressions of MMP-3 and TIMP-1 mRNA in synovium were detected by RT-PCR. Results ①The arthritis indexs of the control group, the methotrexate group, the ^99Tc-MDP group were increased with time. ②The histopathologieal scores of the control group were significantly higher than those of methotrexate group and ^99Tc-MDP group （P〈0.01）. The histopathological scores of cartilage destruction and bone erosion of ^99Tc-MDP group were lower than those of methotrexate group （P〈0.05）. ③The levels of MMP-3 mRNA of the control group, ^99Tc-MDP group, methotrexate group were notably higher than those of the control group （P〈0.01）. The levels of control group was notably higher than that of the ^99Tc-MDP group （P〈0.05）. There was not significant difference in all groups on the levels of TIMP-1 mRNA （P〉0.05）. ConcIusions ^99Tc-MDP can notably relieve the arthritis symdrome and retard the catilage damage and bone erosion of CIA in rats, and could significantly decrease the MMP-3 mRNA in the synovium. Which may be one of the therapeutic mechanism;^99Tc-MDP is better than methotrexate in retarding catilage and bone erosion and decreasing MMP-3 mRNA in CIA rats in a 3-week therapeutic intervention.