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 events 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 TIMP counterregulation. Reepithelialization was found to be associated with active production of collagenase, 92-kDa gelatinase, and stromelysins-1 and -2 by distinct subpopulations of keratinocytes at the migrating border. Notably, no TIMP transcripts were expressed in the epidermis, but TIMP-1 expression in the wound colocalized with expression of collagenase, 92-kDa gelatinase, and stromelysin-1, albeit in distinct cells. Concomitant with the formation of an extensive hyperproliferative epithelium, TIMP-1 transcripts accumulated at the mesenchymal/epidermal border of the granulation tissue. During later phases of wound repair, we observed an increase in 72-kDa gelatinase and MT1-MMP expression, whereby the transcripts of these colocalizing MMPs were detected exclusively 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 levels, whereas the macrophage-specific metalloelastase (MME) reached maximum 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 is known to result in impaired wound healing, led to a nearly complete shut-off of MME expression. These observations imply an additional role of macrophage-related proteolysis, independent of its classical roles during earlier, inflammatory phases of cutaneous wound repair.
Max-Planck-Institut für Biochemie, Martinsried, Germany.
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Madlener
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Parks
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Werner
D000818:Animals; D003907:Dexamethasone / Q000494:pharmacology; D004847:Epithelial Cells / Q000737:chemistry; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D005938:Glucocorticoids / Q000494:pharmacology; D006097:Granulation Tissue / Q000737:chemistry; D015603:Keratinocytes / Q000737:chemistry; D008666:Metalloendopeptidases / Q000032:analysis / Q000235:genetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D012333:RNA, Messenger / Q000032:analysis; D012867:Skin / Q000737:chemistry / Q000201:enzymology; D012879:Skin Physiological Phenomena / Q000235:genetics*; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics*; D014945:Wound Healing / Q000235:genetics*
D005938:Glucocorticoids; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D003907:Dexamethasone; D008666:Metalloendopeptidases