Regulation of matrix biosynthesis and degradation in systemic sclerosis

The regulation of matrix biosynthesis in systemic sclerosis has been the fo cus of many studies, because excessive matrix synthesis causes pathologic c hanges, and because this would seem to be a good target for therapies aimed at ameliorating the disease. Possible targets for antifibrotic therapies i nclude both matrix gene stimulatory and inhibitory pathways. Much recent pr ogress has been made in understanding the mechanism of action of transformi ng growth factor-beta (TGF-beta), an Important profibrotic cytokine with pl eiotropic effects on fibroblasts. It appears that TGF-beta may use multiple signal transduction pathways in fibroblasts and it is possible that defect s in any of these pathways may result in an abnormal response to TGF-beta, resulting in fibrosis. Studies on negative regulation of matrix gene expres sion have singled out the antifibrotic cytokines tumor necrosis factor-alph a and interferon-gamma. Finally, a new approach that compares mRNA expressi on in normal versus diseased fibroblasts has already lead to the discovery of genes that may play a role in the development of fibrosis, This represen ts an important advance because genes can be Identified that have not previ ously been implicated in the control of matrix synthesis, and thus might no t otherwise have been studied in this context. (C) 2000 Lippincott Williams & Wilkins, Inc.