ACTIVATION OF TISSUE INHIBITOR OF METALLOPROTEINASES-3 (TIMP-3) MESSENGER-RNA EXPRESSION IN SCLERODERMA SKIN FIBROBLASTS

Excessive accumulation of fibrillar collagens is a hallmark of the cut aneous fibrosis in both systemic and localized scleroderma. Turnover o f the collagenous extracellular matrix is dependent on the balance bet ween collagenolytic matrix metalloproteinases and their specific inhib itors. We have examined the expression of the novel, matrix associated tissue inhibitor of metalloproteinases-3 (TIMP-3) in normal and scler oderma skin fibroblasts in culture and in vivo. The levels of TIMP-3 m RNA were elevated up to 2.5-fold in five of seven systemic sclerosis f ibroblast strains, whereas TIMP-1 mRNA expression was elevated up to 1 .8-fold in two and TIMP-2 mRNA expression up to 1.8-fold in two system ic sclerosis strains. Using irt situ hybridization, TIMP-3 mRNA was de tected in seven of 12 localized scleroderma skin samples, specifically in fibroblasts within fibrotic collagen fibers or in the vicinity of inflammatory cells. TIMP-1 mRNA was detected in three of eight sclerod erma skin samples in fibroblasts adjacent to inflammatory cells. The e xpression of TIMP-3 mRNA by systemic sclerosis and normal skin fibrobl asts was enhanced to a similar extent (by 8.6- and 8.1-fold, respectiv ely) by transforming growth factor-beta, and suppressed down to 34 and 54%, respectively, by tumor necrosis factor-alpha. Specific activatio n of TIMP-3 gene expression in scleroderma skill fibroblasts in cultur e and itt vivo suggests a role for TIMP-3 in the pathogenesis of derma l fibrosis via inhibition of turnover of fibrotic dermal extracellular matrix, possibly due to upregulation of TIMP-3 expression by transfor ming growth factor-beta.