School of Pharmacy, Sungkyunkwan University, Suwon, Korea.
School of Pharmacy, Sungkyunkwan University, Suwon, Korea Departments of Polymer Science and Chemical Engineering, Sungkyunkwan University, Suwon, Korea.
Ann Rheum Dis. 2015 Jan;74(1):267-74. doi: 10.1136/annrheumdis-2013-203467. Epub 2013 Nov 19.
To test the hypothesis that Notch signalling plays a role in the pathogenesis of rheumatoid arthritis (RA) and to determine whether pharmacological inhibition of Notch signalling with γ-secretase inhibitors can ameliorate the RA disease process in an animal model.
Collagen-induced arthritis was induced in C57BL/6 or Notch antisense transgenic mice by immunisation with chicken type II collagen (CII). C57BL/6 mice were administered with different doses of inhibitors of γ-secretase, an enzyme required for Notch activation, at disease onset or after onset of symptoms. Severity of arthritis was monitored by clinical and histological scores, and in vivo non-invasive near-infrared fluorescence (NIRF) images. Micro-CT was used to confirm joint destruction. The levels of CII antibodies and cytokines in serum were determined by ELISA and bead-based cytokine assay. The expression levels of cytokines were studied by quantitative PCR in rheumatoid synovial fibroblasts.
The data show that Notch signalling stimulates synoviocytes and accelerates their production of proinflammatory cytokines and immune responses involving the upregulation of IgG1 and IgG2a. Pharmacological inhibition of γ-secretase and antisense-mediated knockdown of Notch attenuates the severity of inflammatory arthritis, including arthritis indices, paw thickness, tissue damage and neutrophil infiltration, and reduces the levels of active NF-κB, ICAM-1, proinflammatory cytokines and matrix metalloproteinase-3 activity in the mouse model of RA.
These results suggest that Notch is involved in the pathogenesis of RA and that inhibition of Notch signalling is a novel approach for treating RA.
验证 Notch 信号通路在类风湿关节炎（RA）发病机制中的作用，并确定 Notch 信号通路的 γ-分泌酶抑制剂的药理学抑制是否可以改善动物模型中的 RA 疾病进程。
通过用鸡Ⅱ型胶原（CII）免疫使 C57BL/6 或 Notch 反义转基因小鼠发生胶原诱导性关节炎。在疾病发作或出现症状后，用不同剂量的 Notch 激活所需酶γ-分泌酶抑制剂对 C57BL/6 小鼠进行给药。通过临床和组织学评分以及体内近红外荧光（NIRF）图像监测关节炎的严重程度。使用微 CT 确认关节破坏。通过 ELISA 和基于珠的细胞因子测定法测定血清中 CII 抗体和细胞因子的水平。通过定量 PCR 研究类风湿滑膜成纤维细胞中细胞因子的表达水平。
数据表明 Notch 信号通路刺激滑膜细胞并加速其产生促炎细胞因子和免疫反应，涉及 IgG1 和 IgG2a 的上调。γ-分泌酶的药理学抑制和 Notch 的反义介导敲低可减轻炎症性关节炎的严重程度，包括关节炎指数、爪厚度、组织损伤和中性粒细胞浸润，并降低 RA 小鼠模型中活性 NF-κB、ICAM-1、促炎细胞因子和基质金属蛋白酶-3 活性的水平。
这些结果表明 Notch 参与 RA 的发病机制，抑制 Notch 信号通路是治疗 RA 的新方法。
