MATRIX METALLOPROTEINASES (MMPS) AND THEIR PHYSIOLOGICAL INHIBITORS (TIMPS) ARE DIFFERENTIALLY EXPRESSED DURING EXCISIONAL SKIN WOUND REPAIR

During cutaneous wound healing a number of migratory and remodeling ev ents occur that require the action of matrix metalloproteinases (MMPs) and their natural inhibitors (TIMPs). In this study, we analyzed the temporal and spatial expression patterns of these molecules during the healing of murine excisional skin wounds. Our data imply that defined phases of repair rely on distinct repertoires of MMP activity and TIM P counterregulation. Reepithelialization was found to be associated wi th active production of collagenase, 92-kDa gelatinase, and stromelysi ns-1 and -2 by distinct subpopulations of keratinocytes at the migrati ng border. Notably, no TIMP transcripts were expressed in the epidermi s, but TIMP-1 expression in the wound colocalized with expression of c ollagenase, 92-kDa gelatinase, and stromelysin-l, albeit in distinct c ells. Concomitant with the formation of an extensive hyperproliferativ e epithelium, TIMP-1 transcripts accumulated at the mesenchymal/epider mal border of the granulation tissue. During later phases of wound rep air, we observed an increase in 72-kDa gelatinase and MT1-MMP expressi on, whereby the transcripts of these colocalizing MMPs were detected e xclusively and at high levels in the granulation tissue. At completion of reepithelialization, the expression levels of the MMPs and TIMP-1 seen in epidermal and dermal compartments declined to near-basal level s, whereas the macrophage-specific metalloelastase (MME) reached maxim um expression. In reepithelialized wound tissue, MME transcripts were detected in deep layers of reconstituted dermis and seemed to cluster around vascular structures. Systemic glucocorticoid treatment, which i s known to result in impaired wound healing, led to a nearly complete shut-off of MME expression. These observations imply an additional rol e of macrophage-related proteolysis, independent of its classical role s during earlier, inflammatory phases of cutaneous wound repair. (C) 1 998 Academic Press.