MECHANISMS OF HEPATOCYTE GROWTH-FACTOR STIMULATION OF KERATINOCYTE METALLOPROTEINASE PRODUCTION

Matrix metalloproteinases participate in normal physiologic processes; however, their overproduction has been associated with connective tis sue destruction in a variety of pathological states. Migrating basal k eratinocytes transiently express collagenase-1 during normal cutaneous reepithelialization. However, the overexpression of both collagenase- 1 and stromelysin-1 has been associated with the pathogenesis of chron ic nonhealing ulcers, Aberrant expression of metalloproteinases in inf lammation is mediated, at least in part, by soluble factors. Since hep atocyte growth factor/scatter factor (HGF/SF) has been reported to pro mote keratinocyte migration and proliferation, key events in wound rep air, and since HGF/SF is produced by dermal fibroblasts and its c-Met receptor is expressed by basal keratinocytes in wounded skin, we have studied the effects of HGF/SF upon keratinocyte metalloproteinase expr ession. We have found that HGF/SF can stimulate keratinocyte collagena se-1 and stromelysin-1 production in a dose-dependent and matrix depen dent manner, Expression of 92-kDa gelatinase was not affected by HGF/S F. We determined that HGF/SF regulation of collagenase-1 expression is transcriptionally mediated and requires tyrosine kinase and protein k inase C activaties. HGF/NK1, a naturally occurring, truncated form of HGF/SF, also stimulates collagenase-1 production, but much less effici ently than does the parent molecule, However, HGF/NK2, another HGF/SF splice variant, as well as heparin, potently inhibit HGF/SF-induced co llagenase-1 synthesis, These results indicate that HGF/SF and its natu rally occurring splice variants have diverse biological effects on ker atinocytes and suggest an additional mechanism whereby HGF/SF may regu late keratinocyte function during wound repair.