GELATINASE-A ACTIVATION IS REGULATED BY THE ORGANIZATION OF THE POLYMERIZED ACTIN CYTOSKELETON

Gelatinase A (GL-A) is a matrix metalloproteinase (MMP) involved in bo th connective tissue remodeling and tumor invasion. GL-A activation is mediated by a membrane-type MMP (MT MMP) that cleaves the GL-A propep tide. In this study, we examined the role of the actin cytoskeleton in regulating GL-A activation and MT-MMP-1 expression. Human palmar fasc ia fibroblasts and human fetal lung fibroblasts were cultured on a pla nar substratum or within different types of collagen lattices, Fibrobl asts that formed stress fibers, either on a planar substratum or withi n an attached collagen lattice, showed reduced GL-A activation compare d with fibroblasts lacking stress fibers, within either floating or st ress-released collagen lattices. To determine whether changes in the o rganization of the actin cy toskeleton could promote GL-A activation, fibroblasts with stress fibers were treated with cytochalasin D. Withi n 24 h after treatment, GL-A activation was dramatically increased, As sociated with this GL-A activation was an increase in MT-MMP-1 mRNA as determined by Northern blot analysis. Treatment with nocodazole, whic h induced microtubule depolymerization and cell shape changes without affecting stress fibers, did not promote GL-A activation. These result s suggest that the extracellular matrix and the actin cytoskeleton tra nsduce signals that modulate GL-A activation and regulate tissue remod eling.