Bou-Gharios G, Osman J, Black C, Olsen I
Kennedy Institute of Rheumatology, London, UK.
Clin Chim Acta. 1994 Nov;231(1):69-78. doi: 10.1016/0009-8981(94)90255-0.
Scleroderma (systemic sclerosis: SSc) is an autoimmune disorder in which excessive extracellular matrix is deposited in skin and internal organs. Because of the importance of metalloproteinases in the turnover of connective tissue, in this study we have developed a novel procedure which utilises flow cytometry (FACS) to measure the production of stromelysin (MMP-3), gelatinase A (MMP-2), and the proteinase inhibitor TIMP-1, by SSc skin fibroblasts. In the presence of monensin, which prevents the secretion of these matrix proteins, there was a similar intracellular accumulation of gelatinase A in normal and SSc cells. However, whereas stromelysin levels also increased in the normal cells, no net synthesis could be detected in the SSc fibroblasts. In marked contrast, the synthesis of TIMP-1 was 50% greater in the SSc cells than in the normal fibroblasts. Our results thus show unequivocally, for the first time, that cells from SSc patients simultaneously produce less stromelysin but substantially higher amounts of TIMP-1 than do normal dermal fibroblasts, suggesting that abnormalities in the regulation of the matrix enzymes and their inhibitors play an important part in the molecular pathology of SSc.
硬皮病（系统性硬化症：SSc）是一种自身免疫性疾病，其中过多的细胞外基质沉积在皮肤和内部器官中。由于金属蛋白酶在结缔组织更新中的重要性，在本研究中，我们开发了一种新方法，利用流式细胞术（FACS）来测量硬皮病皮肤成纤维细胞产生基质溶解素（MMP-3）、明胶酶A（MMP-2）和蛋白酶抑制剂TIMP-1的情况。在莫能菌素存在的情况下，莫能菌素可阻止这些基质蛋白的分泌，正常细胞和硬皮病细胞中明胶酶A在细胞内的积累情况相似。然而，正常细胞中的基质溶解素水平也会升高，而在硬皮病成纤维细胞中未检测到净合成。形成鲜明对比的是，硬皮病细胞中TIMP-1的合成比正常成纤维细胞高50%。因此，我们的结果首次明确表明，与正常真皮成纤维细胞相比，硬皮病患者的细胞同时产生较少的基质溶解素，但TIMP-1的量却显著更高，这表明基质酶及其抑制剂调节异常在硬皮病的分子病理学中起重要作用。
