Metalloproteinases and their inhibitors: regulators of wound healing

Abstract

Wound healing is a dynamic process that involves a coordinated response of many cell types representing distinct tissue compartments and is fundamentally similar among tissue types. Among the many gene products that are essential for restoration of normal tissue architecture, several members of the matrix metalloproteinase (MMP) family function as positive and, at times, negative regulators of repair processes. MMPs were initially thought to only function in the resolution phase of wound healing, particularly during scar resorption; however, recent evidence suggests that they also influence other wound-healing responses, such as inflammation and re-epithelialization. In this review, we discuss what is currently known about the function of MMPs in wound healing and will provide suggestions for future research directions.

Figure 1

Varied metalloproteinase functions during wound healing. Shown in this cartoon are some the many functions that MMPs regulate concurrently during tissue repair. A. Cell Migration: MMPs facilitate epithelial cell migration by affecting the interaction between cells and ECM proteins, either by direct proteolysis of the ECM or processing of cell-ECM adhesion proteins on the cell surface. B. Re-epithelialization: Junctional proteins, like E-cadherin, are shed by MMPs, thereby loosening cell-cell adhesions and subsequently, promoting a shift to a repair phenotype, characterized by dedifferentiation, proliferation, and migration. C. Leukocyte Influx: Proteoglycan/chemokine complexes are shed by MMPs from the basolateral cell surface to establish a chemotactic gradient that guides the transepithelial migration of neutrophils. D. Inflammation: MMPs process multiple chemokines with varied results, as shown in Table 1. Among the consequences of chemokine processing are complete degradation, production of a receptor antagonist, inhibition, or activation.