Wound healing is an orderly process, during which the disrupted epithelium is restored by cell migration and proliferation, and the injured tissue is replaced by the newly deposited matrix. Most, if not all the components of the extracellular matrix and the basement membranes can be degraded by matrix metalloproteinases (MMPs). The expression of MMPs is controlled by cytokines, growth factors, oncogenes, and changes in the cell-cell and cell-matrix interactions. Tissue inhibitors of metalloproteinases (TIMPs) -1, -2, -3 and -4, are the most important inhibitors of MMPs, whose activities are required not only to prevent excessive proteolysis of tissues but also to regulate e.g. cell proliferation and angiogenesis. MMPs have been implicated in various physiological and pathological conditions that require remodeling of the extracellular matrix. In dermal wounds, they may serve a role in e.g removing the devitalized tissue, in dissecting the way for migratory cells, or in activating latent growth factors.
Based on our results, migrating keratinocytes express MMPs, collagenase-1 and stromelysin-2, during wound healing. Expression of collagenase-1 is induced rapidly after injury, possibly by the keratinocyte contact to extracellular matrix. Urokinase plasminogen activator, which is expressed by the migrating keratinocytes as well, may lead to plasminogen activation cascade and degradation of the fibronectin and fibrin-rich provisional matrix, together with activation of collagenase-1 and stromelysin-2. Collagenase-1 and stromelysin-1 participate also in the remodeling of the newly deposited connective tissue. Matrilysin is not involved in dermal wound healing.
TIMPs-1 and -3 are expressed by basal keratinocytes further from the migrating front than collagenase-1, where they may act in protecting the re-established basement membrane from degradation. TIMP-1, TIMP-2 and TIMP-3 are expressed also in the matrix, probably neutralizing the MMPs secreted by the epithelial as well as the stromal cells. TIMP-4 appears to play a minor role in human wound healing.
The patterns of MMPs and their inhibitors are qualitatively rather similar in acute and chronic wounds. The major differences include 1) higher quantities of e.g. collagenase-1 mRNA positive epithelial and stromal cells in chronic wounds 2) presence of collagenase-3 mRNA in the stroma of chronic, but not in acute wounds and 3) lack of TIMP-1 and TIMP-3 mRNA expression in proliferating epithelium of chronic wounds.
In active, ulcerative IBD, collagenases-1 and -3 and stromelysin-1 probably participate in matrix remodeling in the granulation tissue beneath the ulcers/erosions. Matrilysin and stromelysin-2 may be needed for the migration of intestinal epithelial cells, while macrophage metalloelastase is involved in macrophage migration. TIMPs-1 and -3 are expressed in stromal areas corresponding to collagenases-1 and -3 and stromelysin-1 expression, while similarly to chronic cutaneous wounds, epithelial cells do not express TIMPs.
In conclusion, successful wound healing is accompanied by tightly scheduled expression of metalloproteinases, their inhibitors and activators. Imbalance of the proteinases and their inhibitors may delay wound healing and result in chronic wounds. MMPs and TIMPs are also involved in both tissue damage and mucosal reparative processes during the course of inflammatory bowel diseases.