Wound healing is a complex process requiring the appropriate temporal and spatial expression of signaling molecules and their receptors, cellular adhesion molecules, and ECM proteins. Together, these molecules regulate the many processes involved in wound healing. Metalloproteinases and their inhibitors are capable of processing many of these signaling molecules, adhesion molecules, and ECM proteins and thus, are likely involved in the control of all aspects of wound healing ().
Metalloproteinase cleavage of signaling molecules and ECM proteins occurs during the inflammatory phase, where MMPs, especially MMP1, 3, 7, and 9, are capable of regulating both chemokine activity () and the establishment of chemotactic gradients (). Degradation of cell adhesion molecules as well as ECM proteins by MMPs is also necessary during the repair phase, where MMP1, 7, 9, and 10 are required for cell migration, while the addition of a synthetic metalloproteinase inhibitor leads to impaired cell migration (). MMPs are also required for cell proliferation during this phase and the demonstration that TIMP3 can regulate angiogenesis suggests that it may also be integral to the maintenance of granulation tissue once it has formed. Finally, wound contraction during the resolution phase requires appropriate expression of MMPs and their inhibitors. MMP3 is required for wound contraction to occur and either the loss of MMP3 or the addition of a synthetic inhibitor of metalloproteinases results in slowed wound contraction.
The current literature offers a great deal of evidence that metalloproteinases and their inhibitors are required for wound healing, and this evidence provides a strong foundation for the continuation of this work. Based on the literature, one of the most plausible roles for MMPs and ADAMS, as well as TIMPs, in wound healing is in control of the inflammatory response. Metalloproteinases and their inhibitors play an integral role in regulating inflammation through both the regulation of chemokine and cytokine activity and signaling gradients, and through regulation of inflammatory-endothelial cell adhesion receptor interaction. One well established way that metalloproteinases are involved in inflammation is through direct interaction with chemokines or their receptors; however, much work still remains to examine the rest of the chemokines involved in the inflammatory response. Another focus of the research should be to examine the interaction between metalloproteinases and mediators of chemokine signaling, such as the syndecans. Syndecans are involved in the regulation of chemokine signaling through sequestration of chemokines within the ECM and by presentation of the chemokine to its receptor on the inflammatory cell surface. Processing of syndecan by metalloproteinases provides an indirect method of regulating chemokine activity. Importantly, further understanding of the role of metalloproteinases and their inhibitors in inflammation will not only further our understanding of wound healing, but also of many other pathological processes, including cancer and inflammatory diseases such as arthritis.
Although the goal of medical research is to identify therapeutic interventions for the disease and molecule of interest, much remains to be understood before this should be considered with metalloproteinases and wound healing. Further work utilizing different models of wound healing in mice with gain- and loss-of-function mutations for MMPs, ADAMs, or TIMPs must occur. These experiments will undoubtedly further our knowledge of how metalloproteinases and their inhibitors control the cellular processes involved in wound repair and help to determine the conditions that are required for them to be either positive or negative regulators of these processes.
Thus, although a great deal of work remains to be done, the ability of MMPs and ADAMs to regulate the activity of bioactive molecules, such as growth factors, cytokines and chemokines, as well as the role of MMPs in digestion of both cell adhesion molecules and ECM proteins in the basement membrane suggests an integral role for these enzymes in all phases of wound healing.