Metalloproteinases and Wound Healing

Abstract

Significance: Matrix metalloproteinases (MMPs) are present in both acute and chronic wounds. They play a pivotal role, with their inhibitors, in regulating extracellular matrix degradation and deposition that is essential for wound reepithelialization. The excess protease activity can lead to a chronic nonhealing wound. The timed expression and activation of MMPs in response to wounding are vital for successful wound healing. MMPs are grouped into eight families and display extensive homology within these families. This homology leads in part to the initial failure of MMP inhibitors in clinical trials and the development of alternative methods for modulating the MMP activity. MMP-knockout mouse models display altered wound healing responses, but these are often subtle phenotypic changes indicating the overlapping MMP substrate specificity and inter-MMP compensation. Recent Advances: Recent research has identified several new MMP modulators, including photodynamic therapy, protease-absorbing dressing, microRNA regulation, signaling molecules, and peptides. Critical Issues: Wound healing requires the controlled activity of MMPs at all stages of the wound healing process. The loss of MMP regulation is a characteristic of chronic wounds and contributes to the failure to heal. Future Directions: Further research into how MMPs are regulated should allow the development of novel treatments for wound healing. SCOPE AND SIGNIFICANCEThis review highlights recent advances in understanding the regulation of matrix metalloproteinases (MMPs) in skin and how this knowledge might be applied in patients to improve wound healing. Selected recent advances include microRNA (MiR) regulation, novel peptides, signal transduction, experimental therapies, and novel dressings. TRANSLATIONAL RELEVANCEWound healing is a complex multicellular process involving fibroblasts, keratinocytes, and endothelial cells as well as inflammatory cells. The healing process follows an orderly sequence of events incorporating four distinct, yet overlapping, phases: hemostasis, the inflammatory phase, the proliferation phase, and the remodeling phase. The phases of wound healing are regulated by cross talk between different groups of molecules, including extracellular matrix (ECM), integrins, growth factors, and MMPs. Migration of cells on ECM, and remodeling and degradation of the ECM by MMPs are key elements of wound repair. CLINICAL RELEVANCEChronic wounds, including pressure sores, venous ulcers, and diabetic ulcers, are a major clinical problem with considerable morbidity and associated financial costs. Excessive MMPs are a feature of chronic wounds. Regulation of MMP levels in wounds could lead to improved wound healing. OVERVIEWThe MMP family is a group of calcium-dependent zinc-containing enzymes that are involved in the degradation of ECM. Family members share structural ( Fig. 1) and sequence similarities, a flexible proline-rich hinge region, and a hemopexinlike C-terminal domain, which functions in recognition of substrates (usually ECM). Excep...

Matrix metalloproteinases in the wound microenvironment: therapeutic perspectives

“…49 The MMP-2 activity remains fairly stable until the phase of reepithelialization. 50,51 MMP-9 contributes to wound healing by initiation of keratinocytes migration and mobilization of endothelial progenitor cells from the bone marrow. In murine model of wound healing, mice lacking MMP-9 showed reduced endothelial progenitor cell mobilization and vasculogenesis in damaged tissue.…”

Tropical ulcer plant treatments used by Papua New Guinea's Apsokok nomads

“…In an in vivo context a plant sap could be present at concentrations as high as 50% v/v suggesting near complete inhibition of MMP activity could be achieved. Initially this may provide a therapeutic benefit, by for example reducing proteolytic cleavage of collagen, but in the longer term, controlled MMP activity is necessary for wound remodelling, therefore complete inhibition may impair wound healing (Caley et al, 2015).…”

Generation of anti-inflammatory macrophages for implants and regenerative medicine using self-standing release systems with a phenotype-fixing cytokine cocktail formulation

“…For example, elevated presence of MMP-7 in the tissue and plasma was associated with impaired wound healing in patients with periodontitis and combat wounds [22,23]. At the same time MMPs are necessary for matrix remodeling and cell migration during wound closure [28]. MMP-7 was shown to be involved in re-epithelization after injury and facilitated cell migration through matrix degradation.…”