INTEGRIN ALPHA-2-BETA-1-DEPENDENT CONTRACTION OF FLOATING COLLAGEN GELS AND INDUCTION OF COLLAGENASE ARE INHIBITED BY TYROSINE KINASE INHIBITORS

A cell culture inside a three-dimensional gel of fibrillar collagen is an experimental model used to study the response of cells to the extr acellular matrix. Many cell types induce the contraction of gel and si multaneously decrease their production of type I collagen, whereas the expression of interstitial collagenase (matrix metalloproteinase-l; M MP-1) is enhanced. me have previously shown that in osteogenic cells t he collagen receptor alpha 2 beta 1 integrin is a positive regulator o f MMP-1 and that the number of alpha 2 beta 1 integrins on the cell su rface also regulates the magnitude of contraction. However, the downre gulation of collagen mRNA levels is not initiated by alpha 2 beta 1 in tegrin. Here, we have studied in human KHOS-240 and MG-63 osteosarcoma cells and in human skin fibroblasts the effects of tyrosine kinase in hibitors on collagen gel contraction and on the regulation of MMP-1 an d collagen alpha 1(I) genes by extracellular collagen. The induction o f MMP-1 could be inhibited by all tyrosine kinase inhibitors tested wi th the exception of genistein. None of them could prevent the downregu lation of collagen expression. Thus, the collagen-induced alterations in the expression of MMP-1 and collagen alpha 1(I) seem to be dependen t on distinct signal transduction pathways. Many of the inhibitors, in cluding genistein, could prevent the contraction of collagen gels. The effect was not related to their ability to inhibit cell growth, becau se an inhibitor specific for DNA synthesis and cell division did not h ave the same effect. Thus, we suggest that the process of collagen gel contraction requires protein-tyrosine phosphorylation and that the ab ility of cells to contract collagen gels is not related to the inducti on of MMP-1 or to the level of collagen alpha 1(I) expression. Finally , we propose that the tyrosine kinase inhibitors might be considered a s candidate molecules in the treatment of pathological scar contractio n. (C) 1996 Academic Press, Inc.