In all forms of cutaneous wounds, collagenase-1 (matrix metalloproteinase-1 (MMP-1)) is invariably expressed by basal keratinocytes migrating over the dermal matrix. We report that native type I collagen mediates induction of MMP-1 by primary human keratinocytes. Collagen-mediated induction of MMP-1 was rapid, being detected 2 h after plating, and was transcriptionally regulated. As demonstrated by in situ hybridization, only migrating keratinocytes expressed MMP-1, suggesting that contact with collagen is not sufficient to induce MMP-1 expression in keratinocytes; the cells must also be migrating. Upon denaturation, type I collagen lost its ability to induce MMP-1 expression but still supported cell adhesion. Other dermal or wound matrix proteins, such as type III collagen, fibrin, and fibronectin, and a mixture of basement membrane proteins did not induce MMP-1 production. In the presence of collagen, laminin-1 inhibited induction of MMP-1 but laminin-5 did not. Taken together, these observations suggest that as basal keratinocytes migrate from the basal lamina onto the dermal matrix contact with native type I collagen induces MMP-1 expression. In addition, our findings suggest that re-establishment of the basement membrane and, in particular, contact with laminin-1 provides a potent signal to down-regulate MMP-1 production as the epithelium is repaired.Normal cutaneous wound healing, as well as healing in essentially all tissues, involves an orderly progression of events to re-establish the integrity of the injured tissue. The initial injury starts a programmed series of interdependent yet functionally separate responses, such as re-epithelialization and epithelial proliferation, inflammation, angiogenesis, fibroplasia, matrix accumulation, and eventually resolution. During each stage in this process, proteinases are needed to remove or remodel extracellular matrix components in both the epithelial and interstitial compartments to accommodate cell migration and tissue repair (1).In a thorough examination of normally healing wounds and of a variety of chronic ulcers, we found that collagenase-1, a member of the matrix metalloproteinase (MMP) 1 family with the ability to cleave fibrillar collagens type I, II, and III at a specific locus in their triple helical domain, is invariably expressed by basal keratinocytes at the edge of repairing tissue (2-4). In all, we have examined Ͼ100 different human skin specimens, representing a variety of chronic ulcers, blisters, and normally healing wounds, and in each sample with injury that breached the basement membrane, collagenase-1 was prominently and invariantly expressed by basal keratinocytes migrating over the dermal wound bed. The invariable expression of collagenase-1 in all forms of wounds and the confinement of its expression to periods of active re-epithelialization suggest that this enzyme plays a critical role in keratinocyte function during healing. Indeed, we recently demonstrated that keratinocyte migration on a native collagen matrix requires the catalyti...