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Angiogenic action of gliostatin in rheumatoid arthritis and its molecular mechanism

胶质抑素对类风湿性关节炎的血管生成作用及其分子机制

基本信息

批准号：
16591504
负责人：
NAGAYA Yuko
金额：
$ 1.73万
依托单位：
NAGOYA CITY UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16591504/
关键词：
rheumatoid arthritis synoviocytes angiogenesis gliostatin VEGF DNA microarray system gene transfection

项目摘要

Neovascularization, proliferation of synovial cells, and mononuclear cell influx and activation are characteristic events observed in synovial joints in the pathohistology of rheumatoid arthritis (RA). We have previously measured the concentration of the angiogenic factor, gliostatin (GLS), in sera and synovial fluids of RA patients, and demonstrated for the first time an enormously high concentration in RA synovial fluids as well as in RA sera. Furthermore our previous study demonstrated that GLS acts as a cytokine to augment its own synthesis in fibroblast-like synoviocytes (FLSs) obtained from patients with RA through an autocrine mechanism. It should be noted that GLS additionally caused induction and extracellular secretion of matrix metalloproteinase (MMP)-1 and MMP-3 triggering cartilage degeneration. Recently we reported that intraarticular injection of rHuGLS to rabbit knees induced RA-like synovitis.The purpose of this study was to elucidate whether GLS/TP is involved in the regulation of the angiogenic cytokine vascular endothelial growth factor (VEGF) in rheumatoid arthritis (RA). Fibroblast-like synoviocytes (FLSs) from patients with RA were cultured and stimulated with recombinant human GLS (rHuGLS) and interleukin (IL)-1β. Immunohistochemistry showed that GLS/TP and VEGF were detectable in the synovial lining cells. In cultured FLSs, both VEGF mRNA and protein levels were markedly increased by rHuIL-1βtreatment. rHuGLS increased VEGF mRNA expression in a dose-dependent manner. We detected high concentrations of VEGF165 protein in culture supernatants from FLSs treated with rHuGLS (300ng/ml), which were comparable to GLS levels found in synovial fluid of RA patients. These findings indicate that GLS/TP and VEGF have synergistic effects on angiogenesis in rheumatoid synovitis, and that GLS/TP has a role in regulating VEGF.

在类风湿关节炎（RA）的病理组织学中，在滑膜关节中观察到的特征性事件是新血管形成、滑膜细胞增殖以及单核细胞流入和活化。我们以前测量了血管生成因子，胶质细胞生长抑制素（GLS），在RA患者的血清和滑液的浓度，并首次证明了一个非常高的浓度在RA滑液以及RA血清。此外，我们以前的研究表明，GLS作为一种细胞因子，以增加其自身的合成在成纤维细胞样滑膜细胞（FLS）从RA患者获得通过自分泌机制。应该注意的是，GLS另外引起基质金属蛋白酶（MMP）-1和MMP-3的诱导和细胞外分泌，从而触发软骨退变。最近我们报道了rHuGLS诱导的类风湿性关节炎（RA）滑膜炎，本研究旨在探讨GLS/TP是否参与了类风湿性关节炎（RA）中血管生成因子血管内皮生长因子（VEGF）的调节。用重组人GLS（rHuGLS）和白细胞介素（IL）-1β刺激RA患者的成纤维样滑膜细胞（FLS）。免疫组化显示滑膜衬里层细胞表达GLS/TP和VEGF。在培养的FLS中，VEGF mRNA和蛋白水平均被rHuIL-1β处理显著增加。rHuGLS以剂量依赖性方式增加VEGF mRNA表达。我们在用rHuGLS（300 ng/ml）处理的FLS的培养上清液中检测到高浓度的VEGF 165蛋白，其与RA患者滑液中发现的GLS水平相当。这些结果表明，GLS/TP和VEGF对类风湿性滑膜炎的血管生成具有协同作用，并且GLS/TP具有调节VEGF的作用。