NF-AT5 is a critical regulator of inflammatory arthritis.
NF-AT5 is a critical regulator of inflammatory arthritis.
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DOI：
10.1002/art.30229
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发表时间：
2011-07
影响因子：
--
通讯作者：
Kim WU
中科院分区：
文献类型：
--
作者：
Yoon HJ;You S;Yoo SA;Kim NH;Kwon HM;Yoon CH;Cho CS;Hwang D;Kim WU
为探讨活化T细胞核因子5（nuclear factor of activated T cells 5，NFAT 5）在类风湿关节炎（rheumatoid arthritis，RA）滑膜增生和血管生成中的作用，采用免疫组化和Western blot方法分别检测RA患者滑膜组织和滑膜细胞中NFAT 5的表达。利用基因芯片技术分析转染假siRNA和NFAT 5 siRNA的RA滑膜细胞和人脐静脉内皮细胞（HUVEC）的mRNA。在NFAT 5 siRNA存在的情况下进行测定滑膜细胞凋亡和增殖的试验，通过测量HUVEC的增殖、管形成和创伤迁移来评估VEGF 165诱导的血管生成。通过注射抗II型胶原抗体诱导小鼠实验性关节炎。NFAT 5在类风湿性关节炎滑膜中高度表达，其活性可被促炎细胞因子如IL-1β和TNF-α增加。用NFAT 5靶向siRNA转染的滑膜细胞和HUVEC的mRNA表达谱揭示了与RA发病机制相关的细胞过程中的三个主要变化：细胞周期和存活、血管生成和细胞迁移。与这些结果一致，RA滑膜细胞和HUVEC中的NFAT 5敲低抑制了它们的增殖/存活并阻碍了HUVEC中的血管生成过程。在组织学分析中，具有NFAT 5单倍体不足（NFAT 5 +/-）的小鼠产生非常有限程度的滑膜增殖，减少血管生成，并且表现出对实验诱导的关节炎的几乎完全抑制。NFAT 5调节慢性关节炎中的滑膜增殖和血管生成。
To investigate the role of nuclear factor of activated T cells 5 (NFAT5), which is known as an osmoprotective transcription factor, in synovial hyperplasia and angiogenesis in rheumatoid arthritis (RA) Expression of NFAT5 was examined in the synovial tissues and synoviocytes of RA patients using immunohistochemistry and Western blot analysis, respectively. The mRNAs of RA synoviocytes and human umbilical vein endothelial cells (HUVEC) transfected with dummy siRNA or NFAT5 siRNA were profiled using microarray technology. Assays to determine synoviocyte apoptosis and proliferation were performed in the presence of NFAT5 siRNA.VEGF165-induced angiogenesis was assessed by measuring the proliferation, tube formation, and wounding migration of HUVEC. Experimental arthritis was induced in mice by injection of anti-type II collagen antibody. NFAT5 was highly expressed in the rheumatoid synovium and its activity was increased by proinflammatory cytokines, such as IL-1β and TNF-α. The mRNA profiling of synoviocytes and HUVEC transfected with NFAT5-targeted siRNA revealed three major changes in cellular processes associated with the pathogenesis of RA: cell cycle and survival, angiogenesis, and cell migration. Consistent with these results, NFAT5 knock-down in RA synoviocytes and HUVEC inhibited their proliferation/survival and impeded angiogenic processes in HUVEC. Mice with NFAT5 haplo-insufficiency (NFAT5+/-) developed very limited degree of synovial proliferation in histological analysis, decreased angiogenesis, and exhibited a nearly complete suppression of experimentally induced arthritis. NFAT5 regulates synovial proliferation and angiogenesis in chronic arthritis.