TNF-α-siRNA联合骨髓间充质干细胞对大鼠类风湿关节炎治疗效果的研究

Therapeutic effect of TNF-α-siRNA combining with bone marrow mesenchymal stem cells transplantation on rat rheumatoid arthritis

抑制患者体内肿瘤坏死因子α(TNF-α)的表达可作为治疗类风湿关节炎(RA)的重要途径。以鸡Ⅱ型胶原法诱导的RA模型大鼠为研究对象,探讨TNF-α-siRNA联合骨髓间充质干细胞(BMSCs)移植治疗RA的效果及其作用机制。RA大鼠随机分为PBS组(模型对照)、甲氨蝶呤组(阳性药物对照)、BMSCs移植组、TNF-α-siRNA注射组和TNF-α-siRNA+BMSCs移植治疗组共5个组。结果表明:与PBS组模型大鼠相比,4个治疗组大鼠的生长速度均极显著提高,而血清中TNF-α、IL-1β水平、足趾肿胀值及强迫游泳不动时间均极显著降低。进一步研究表明,与PBS组模型大鼠相比,基质金属蛋白酶抑制剂(TIMP-1)表达水平在4个治疗组均极显著提高,而基质金属蛋白酶9 (MMP-9)的表达水平均极显著降低;TNF-α-siRNA+BMSCs联合治疗效果显著优于其他治疗组。这一研究说明,TNF-α-siRNA+BMSCs联合治疗可能通过抑制RA关节处MMP-9的表达而发挥作用,从而为基因干扰联合干细胞移植治疗RA提供了重要的试验依据。

Inhibiting the expression of tumor necrosis factor alpha(TNF-α) in patients can be served as an important way to treat rheumatoid arthritis(RA). In this study, chicken type II collagen induced RA model rats were used to determine the therapeutic effects of TNF-α-siRNA combining with bone marrow mesenchymal stem cells(BMSCs) transplantation on RA. RA rats were randomly divided into five groups: PBS(control group), methotrexate(positive drug group), BMSCs transplantation group, TNF-α-siRNA injection group, and TNF-α-siRNA+BMSCs transplantation group. The results showed that compared with PBS rats, the growth rate and the struggle time of forced swim test of the four treatment groups were all significantly increased(P<0.01), while the serum TNF-α and IL-1β levels, the foot swelling value and the immobility time of forced swim test were significantly reduced(P<0.01). Further results showed that compared with PBS rats, matrix metalloproteinase inhibitor(TIMP-1) expression was significantly increased(P<0.01), while the expression level of matrix metalloproteinase 9(MMP-9) was significantly reduced(P<0.01) in the four treatment groups.Furthermore,the TNF-α-siRNA+BMSCs transplantation group showed a better therapeutic effect than the other treatment groups.The results showed that the co-transplantation of TNF-α-siRNA+BMSCs may exert an better therapeutic effect by inhibiting MMP-9 expression in RA joints,so as to provide an important experimental basis for gene interference combining with stem cell transplantation on RA.