Shi Juan, Diao Zhijuan, Zhou Jiansuo, Zhu Jieqing, Yuan Haiqin, You Xin, Liu Yanxin, Zheng Dexian
Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Arthritis Rheum. 2012 May;64(5):1345-54. doi: 10.1002/art.33492.
Synovial cells in rheumatoid synovium display abnormal proliferation, which leads to joint destruction. TRAIL has been described as a proapoptotic factor in fibroblast-like synoviocytes (FLS). This study was undertaken to investigate the functions of rAAV2/5-TRAIL in human FLS and in arthritic mice.
Primary human FLS were infected with rAAV2/5-TRAIL in the presence or absence of epirubicin. Transgene expression was monitored by both enzyme-linked immunosorbent assay and flow cytometry. The disease-modulating activity of epirubicin plus rAAV2/5-TRAIL was investigated in mice with collagen-induced arthritis (CIA).
Subtoxic doses of epirubicin potentiated rAAV2/5-mediated TRAIL expression in FLS and simultaneously enhanced the sensitivity of FLS to TRAIL. Epirubicin treatment up-regulated death receptor 4 (DR-4) and DR-5 expression and down-regulated FLIP expression, thereby enhancing the activation of procaspase 3, procaspase 8, and procaspase 9. An in vivo study showed that the combination of rAAV2/5-TRAIL gene therapy and epirubicin chemotherapy provided augmented antiarthritic effects in a mouse model of CIA. The intraarticular injection of rAAV2/5-TRAIL combined with epirubicin treatment significantly reduced the severity and incidence of CIA and joint swelling in the animals. Histologic evaluations revealed that inflammatory cell infiltration, cartilage destruction, and bone erosion were significantly reduced in the joints of the mice receiving the synthetic treatment. Results of a viral genome copy number assay indicated that epirubicin dramatically augmented the expression of rAAV2/5-TRAIL without altering its tissue distribution.
These results suggest that epirubicin enhances the antiarthritic effect of rAAV2/5-TRAIL and that combination treatment might be an important therapeutic alternative, with practical significance for rheumatoid arthritis.
类风湿性滑膜中的滑膜细胞表现出异常增殖，这会导致关节破坏。TRAIL已被描述为成纤维样滑膜细胞（FLS）中的促凋亡因子。本研究旨在探讨重组腺相关病毒2/5-TRAIL（rAAV2/5-TRAIL）在人FLS和关节炎小鼠中的作用。
在有或没有表柔比星的情况下，用rAAV2/5-TRAIL感染原代人FLS。通过酶联免疫吸附测定和流式细胞术监测转基因表达。在胶原诱导的关节炎（CIA）小鼠中研究表柔比星加rAAV2/5-TRAIL的疾病调节活性。
亚毒性剂量的表柔比星增强了rAAV2/5介导的FLS中TRAIL的表达，同时增强了FLS对TRAIL的敏感性。表柔比星治疗上调了死亡受体4（DR-4）和DR-5的表达，并下调了FLIP的表达，从而增强了半胱天冬酶原3、半胱天冬酶原8和半胱天冬酶原9的激活。一项体内研究表明，rAAV2/5-TRAIL基因治疗和表柔比星化疗的联合应用在CIA小鼠模型中提供了增强的抗关节炎作用。关节内注射rAAV2/5-TRAIL联合表柔比星治疗显著降低了CIA的严重程度和发病率以及动物的关节肿胀。组织学评估显示，接受联合治疗的小鼠关节中的炎性细胞浸润、软骨破坏和骨侵蚀明显减少。病毒基因组拷贝数测定结果表明，表柔比星显著增强了rAAV2/5-TRAIL的表达，而不改变其组织分布。
这些结果表明，表柔比星增强了rAAV2/5-TRAIL的抗关节炎作用，联合治疗可能是一种重要的治疗选择，对类风湿性关节炎具有实际意义。
