Role of matrix metalloproteinases in diabetic foot ulcers: Potential therapeutic targets

Abstract

Diabetic foot ulcers (DFUs) are pathological states of tissue destruction of the foot or lower extremity in diabetic patients and are one of the serious chronic complications of diabetes mellitus. Matrix metalloproteinases (MMPs) serve crucial roles in both pathogenesis and wound healing. The primary functions of MMPs are degradation, which involves removing the disrupted extracellular matrix (ECM) during the inflammatory phase, facilitating angiogenesis and cell migration during the proliferation phase, and contracting and rebuilding the tissue during the remodeling phase. Overexpression of MMPs is a feature of DFUs. The upregulated MMPs in DFUs can cause excessive tissue degradation and impaired wound healing. Regulation of MMP levels in wounds could promote wound healing in DFUs. In this review, we talk about the roles of MMPs in DFUs and list potential methods to prevent MMPs from behaving in a manner detrimental to wound healing in DFUs.

A purified reconstituted bilayer matrix shows improved outcomes in treatment of non‐healing diabetic foot ulcers when compared to the standard of care: Final results and analysis of a prospective, randomized, controlled, multi‐centre clinical trial

“…An additional consideration with regard to wound healing would relate to the role that matrix metalloproteinases (MMP) play in healing. It is known that these proteases play a key role in the degradation and remodelling of the extracellular matrix (ECM) during wound healing 28 . The wound healing process can thus be hindered by a number of biochemical or physiological processes, whether prolonged inflammation, imbalance in ECM synthesis and degradation, poor neovascularization, or impaired macrophage activity 29 .…”

Approaches to Control and Monitor Protease Levels in Chronic Wounds

“…Last year, 2 review papers related to this topic were published that interested readers could refer to for more information; [ 26,63 ] here, this subject is discussed briefly and with a different perspective from that of other publications.…”

“…[23] In the human and animal body, proteases are secreted by a variety of cells, including inflammatory cells, such as neutrophils, macrophages, and mast cells, as well as non-inflammatory cells, such as epithelial cells, endothelial cells, keratinocytes, and fibroblasts. [24] The following paragraph briefly reviews some roles of proteases whose names have been mentioned in the current article; it is not an exhaustive review; interested readers could refer to other review articles [25][26][27][28][29][30][31] to get more insights on this topic. However, it should be noted that hardly any proven mechanism for the modes of action of proteases in wound healing could be found.…”

Nanozymes for the Therapeutic Treatment of Diabetic Foot Ulcers

“…In addition to endogenous proteases, microorganisms colonizing the periwound also express exogenous proteases to promote their proliferation and exacerbate the infection. 65 Overall, high levels of endogenous and exogenous proteases in the DFU microenvironment are powerful "catabolizers" that continuously break down the ECM and further degrade already insufficiently supplied growth factors, accompanied by a large amount of proteinous exudates, leading to wound healing failure. High levels of MMPs also decrease VEGF expression and inhibit fibroblast growth.…”