EXCESS MATRIX ACCUMULATION IN SCLERODERMA IS CAUSED PARTLY BY DIFFERENTIAL REGULATION OF STROMELYSIN AND TIMP-1 SYNTHESIS

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.