Matrix metalloproteinase 2 (gelatinase A) is related to migration of keratinocytes

The role of matrix metalloproteinases (MMPs) in cell migration was studied by measuring cell growth, migration, and production of MMP-2 and -9 in oral mucosal and skin keratinocytes cultured in the presence of synthetic MMP i nhibitors. MMP-2 was the major gelatinolytic MMP produced by these cells wh ile MMP-9 was produced at a low basal level. Inhibitor effects on MMP-9 pro duction were therefore studied in keratinocytes stimulated by tumor necrosi s factor alpha (TNF alpha), Tetracycline analogues at concentrations that i nhibited the production of MMP-2 but not MMP-9 were able to drastically inh ibit migration of both mucosal and skin keratinocytes. Tetracycline analogu es also inhibited keratinocyte growth, an effect not found for the other in hibitors tested. Heterocyclic carbonate-derived compounds (LWs) that inhibi ted MMP-9 but not MMP-2 production had no effect on cell migration. Batimas tat, a potent MMP inhibitor, did not have any effect on MMP production or c ell growth but did inhibit keratinocyte migration. Tumor growth factor beta (TGF beta) increased keratinocyte migration as well as both cell-associate d and secreted MMP-2 production in wounded cell cultures. The secreted enzy me was partially converted into an active form. In this model batimastat to tally blocked TGF beta-promoted keratinocyte migration. Immunostaining of k eratinocytes advancing into the wound revealed that MMP-2 was localized in extracellular matrix contactlike structures against the endogenously produc ed laminin-Ei-rich matrix. MMP-9 was localized diffusely along the cell mem branes. Using in situ hybridization we observed that in chronically inflame d human gingiva MMP-2 is expressed in epithelium extending into subepitheli al connective tissue, These results suggest that MMP-2 plays a specific rol e in epithelial migration, possibly by detaching the advancing cells from t he pericellular matrix or by activating other MMPs. (C) 1999 Academic Press .