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Suppressive autoantibodies in rheumatoid arthritis : construction of gene-modified animals and analysis of their arthrapathy

类风湿性关节炎的抑制性自身抗体：基因修饰动物的构建及其关节病分析

基本信息

批准号：
13557041
负责人：
OZAKI Shoichi
金额：
$ 10.18万
依托单位：
St.Marianna University School of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2001
资助国家：
日本
起止时间：
2001 至 2003
项目状态：
已结题

项目摘要

We isolated folistatin-related protein (FRP) as a novel autoantigen of rheumatoid arthritis. In order to clarify its pathological role, we tried to construct FRP-transgenic mouse, which is now under way, and tried to elucidate the in vitro and in vivo functions of FRP for synovial cells and their inflammation.Transforming growth factor (TGF)-beta augmented FRP gene expression in synovial cells. FRP reduced synovial production of matrix metalloproteinase (MMP)1, MMP3 and prostaglandin E2, potent agonists of joint construction in RA. In contrast, autoantibodies to FRP from patients with RA increased their production by blocking FRP activity, probably in the autocrine system. Moreover, FRP down-regulated synovial expression of FOS (c-fos), which seemed responsible for the reduction in MMP1 and MMP3 caused by FRP.We investigated the roles of FRP in a mouse model of arthritis, which was induced in BALB/c mice by injecting anti-type II collagen monoclonal antibody and lipopolysaccharide. Mice were treated with daily intraperitoneal injections of 20 μg of recombinant FRP. This treatment showed significant amelioration of the arthritis severity. Histologic analyses confirmed this finding and revealed the alleviation of cellular infiltration into the synovium as well as cartilage damage. Moreover, array analysis of the gene expression profile in FPR-treated arthritic lesions revealed a reduced expression of the c-fos, ets-2, IL6, MMP3, and MMP9 genes, some of which are thought to be associated with synovial inflammation and joint destruction.These findings from in vitro and in vivo experiments suggest that FRP could be one of the key molecules in the treatment of inflammatory joint diseases such as RA.

我们分离到一种新的类风湿关节炎自身抗原--叶酸相关蛋白（FRP）。为了阐明FRP的病理作用，我们尝试构建FRP转基因小鼠（目前正在进行中），并试图阐明FRP在滑膜细胞及其炎症中的体内外功能，转化生长因子（transforminggrowthfactor，TGF）-β增强滑膜细胞FRP基因表达。FRP减少滑膜生产的基质金属蛋白酶（MMP）1，MMP 3和前列腺素E2，在RA关节建设的有效激动剂。相反，来自RA患者的FRP自身抗体通过阻断FRP活性而增加其产生，可能是在自分泌系统中。此外，FRP下调滑膜FOS（c-fos）的表达，这可能是FRP引起的MMP 1和MMP 3的减少的原因。我们研究了FRP在通过注射抗II型胶原单克隆抗体和脂多糖诱导的BALB/c小鼠关节炎模型中的作用。每天腹膜内注射20 μg重组FRP处理小鼠。该治疗显示关节炎严重程度的显著改善。组织学分析证实了这一发现，并揭示了减轻细胞浸润到滑膜以及软骨损伤。此外，基因表达谱的阵列分析显示，在FPR治疗的关节炎病变的c-fos，ets-2，IL 6，MMP 3和MMP 9基因的表达减少，其中一些被认为是与滑膜炎症和关节damage.These在体外和体内实验的结果表明，FRP可能是在治疗炎症性关节疾病，如RA的关键分子之一。