DIFFERENTIAL-EFFECTS OF TRANSFORMING-GROWTH-FACTOR-BETA ON THE EXPRESSION OF COLLAGENASE-1 AND COLLAGENASE-3 IN HUMAN FIBROBLASTS

Collagenase-3 (MMP-13) is a matrix metalloproteinase (MMP) originally identified in breast carcinomas which is also produced at significant levels during fetal ossification and in arthritic processes. In this w ork, we have found that transforming growth factor beta 1 (TGF-beta 1) , a growth factor widely assumed to be inhibitory for MMPs, strongly i nduces collagenase-3 expression in human KMST fibroblasts. In contrast , this growth factor down-regulated the expression in these cells of c ollagenase-1 (MMP-1), an enzyme highly related to collagenase-3 in ter ms of structure and enzymatic properties. The positive effect of TGF-b eta 1 on collagenase-3 expression was dose-and time-dependent, but ind ependent of the effects of this growth factor on cell proliferation ra te. Analysis of the signal transduction mechanisms underlying the up-r egulating effect of TGF-beta 1 on collagenase-3 expression demonstrate d that this growth factor acts through a signaling pathway involving p rotein kinase C and tyrosine kinase activities. Functional analysis of the collagenase-3 gene promoter region revealed that the inductive ef fect of TGF-beta 1 is partially mediated by an AP-1 site. Comparative analysis with the promoter region of the collagenase-1 gene which cont ains an AP-1 site at equivalent position, confirmed that TGF-beta 1 di d not have any effect on CAT activity levels of this promoter. Finally , by using electrophoretic mobility shift assays and antibody supershi ft analysis, we propose that c-Fos, c-Jun, and JunD may play major rol es in the collagenase-3 activation by TGF-beta 1 in human fibroblasts.