Anti-integrin antibodies induce type IV collagenase expression in keratinocytes

During wound healing, pericellular proteolysis is thought to be essential for the detachment of keratinocytes from basement membrane and in their migration into the wound bed. We have characterized integrin-type cell adhesion/migration receptors in human mucosal keratinocytes and examined their function in the regulation of type IV collagenase gene expression. Two major integrins of the beta 1 class, alpha 2 beta 1 and alpha 3 beta 1, were found to function as collagen and fibronectin receptors, respectively. Antibodies against beta 1 and alpha 3 integrin subunits were found to stimulate the expression of the 92 kDa type IV collagenase severalfold in a dose-dependent manner. Keratinocytes expressed also the 72 kDa type IV collagenase, the synthesis of which remained, however, unchanged in keratinocytes treated with anti-integrin antibodies. Stimulation of 92 kDa enzyme was found to be caused directly by antibody binding to integrins, since Fab-fragments of anti-beta 1 antibodies alone were able to induce collagenase expression in the absence of secondary, clustering antibodies. Antibodies against alpha 2 beta 1 integrin caused no stimulation. Keratinocytes seeded on different substrata (plastic, collagen, fibronectin, laminin, or vitronectin) showed equal induction of type IV collagenase expression. Expression of 92 kDa type IV collagenase could not be induced by peptides (GRGDS, GRGES), proteins (fibronectin, laminin, fibrinogen, albumin), or antibodies to fibronectin. We suggest that proteolytic processes around keratinocytes can be regulated by extracellular factors signalling through integrin-type receptors.