INTEGRIN ALPHA-2-BETA-1 IS A POSITIVE REGULATOR OF COLLAGENASE (MMP-1) AND COLLAGEN ALPHA-1(I) GENE-EXPRESSION

A classical model for studying the effects of extracellular matrix is to culture cells inside a three-dimensional collagen gel. When surroun ded by fibrillar collagen, many cell types decrease the production of type I collagen, and the expression of interstitial collagenase (matri x metalloproteinase-l; MMP-1) is simultaneously induced. To study the role of the collagen-binding integrins (alpha 1 beta 1 and alpha 2 bet a 1 in this process, we used three different osteogenic cell lines wit h distinct patterns of putative collagen receptors: HOS cells, which e xpress only alpha 1 beta 1 integrin, MG-63 cells, which express only a lpha 2 beta 1 integrin, and KHOS-240 cells, which express both. Inside collagen gels, alpha 1(I) collagen mRNA levels were decreased in HOS and KHOS-240 cells but not in MG-63 cells. In contrast, MMP-1 expressi on was induced in KHOS-240 and MG-63 cells but not in HOS cells. Trans fection of MG-63 cells with alpha 2 integrin cDNA produced cell clones overexpressing alpha 2 beta 1 integrin. Transfection of MG-63 cells w ith alpha 2 integrin cDNA in an antisense orientation reduced the expr ession level of alpha 2 integrin. These cell clones showed induction a nd reduction of mRNA levels for MMP-1, respectively. HOS cells normall y lacking alpha 2 beta 1 integrin mere forced to express it, and this prevented the down-regulation in the levels of (alpha 1(I) collagen mR NA when cells were grown inside collagen gels. The data indicate that the level of MMP-1 expression is regulated by the collagen receptor al pha 2 beta 1 integrin. The down-regulation of collagen alpha 1(I) is m ediated by another receptor. Integrin alpha 2 beta 1 may compete with it and thus be a positive regulator of collagen synthesis.