Arthritogenic action of gliostatin in rheumatoid arthritis and its molecular mechanism

新血管形成、滑膜细胞增殖、单核细胞内流和活化是类风湿性关节炎（RA）滑膜关节病理组织学中观察到的特征性事件。我们之前已经测量了血管生成因子胶质抑制素（GLS）在RA患者血清和滑液中的浓度，并首次证明RA滑液和RA血清中的浓度非常高。此外，我们之前的研究表明，GLS作为一种细胞因子，通过自分泌机制增强了从RA患者获得的成纤维细胞样滑膜细胞（FLSs）的自身合成。值得注意的是，GLS还引起基质金属蛋白酶(MMP)-1和MMP-3的诱导和细胞外分泌，从而引发软骨退变。最近我们报道了兔膝关节内注射rHuGLS诱导ra样滑膜炎。本研究的目的是探讨疾病修饰抗风湿药物（DMARDs）是否参与GLS表达的调节。培养FLSs并刺激有或无DMARDs的白细胞介素(IL)-1 β。采用逆转录-聚合酶链反应法和酶联免疫吸附法检测GLS的表达水平。在培养的类风湿FLSs中，GLSmRNA在il -1 β的刺激下明显增加。甲硫葡萄糖和地塞米松使il -1 β刺激的fls中GLSmRNA呈剂量依赖性降低。甲氨蝶呤和柳氮磺胺吡啶对GLS的产生无明显影响。这些发现表明，甲氧基葡萄糖和地塞米松是通过抑制GLS产生介导的抗风湿病活性。

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.