Arthritogenic action of gliostatin in rheumatoid arthritis and its molecular mechanism

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，我们报道了关节内注射rHuGLS到兔膝关节诱导RA样滑膜炎。为探讨疾病修饰抗风湿药物（disease modified antirheumatoid drugs，DMARDs）是否参与了GLS表达的调控，本研究采用体外培养的FLS细胞，在有或无DMARDs的情况下，刺激IL-1 β。GLS的表达水平通过逆转录-聚合酶链反应方法和酶联免疫吸附测定法测定。在培养的类风湿FLSs中，发现IL-1 β刺激显著增加GLSmRNA。金硫葡萄糖和地塞米松以剂量依赖性方式减少IL-1 β刺激的FLS中的GLSmRNA。甲氨蝶呤和柳氮磺胺吡啶对GLS的产生没有明显影响，这些结果表明金硫葡萄糖和地塞米松通过抑制GLS的产生而介导抗风湿活性。

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 investigate whether disease modified antirheumatic drugs (DMARDs) is involved in the regulation of GLS expression.FLSs were cultured and stimulated interleukin (IL)-1beta with or without DMARDs. Expression levels of GLS were determined by reverse transcription-polymerase chain reaction methods and enzyme-linked immunosorbent assays. In cultured rheumatoid FLSs GLSmRNA were found to be markedly increased by stimulation of IL-1beta. GLSmRNA in IL-1beta-stimulated FLSs were reduced by aurothioglucose and dexamethasone in a dose dependent manner. Methotrexate and sulfasalazine had no major influence on GLS production.These findings indicate that aurothioglucose and dexamethasone are responsible for the anti-rheumatic activity mediated via inhibition GLS production.