Targeting matrix metalloproteases in diabetic wound healing

Abstract

Chronic inflammation participates in the progression of multiple chronic diseases, including obesity, diabetes mellitus (DM), and DM related complications. Diabetic ulcer, characterized by chronic wounds that are recalcitrant to healing, is a serious complication of DM tremendously affecting the quality of life of patients and imposing a costly medical burden on society. Matrix metalloproteases (MMPs) are a family of zinc endopeptidases with the capacity of degrading all the components of the extracellular matrix, which play a pivotal part in healing process under various conditions including DM. During diabetic wound healing, the dynamic changes of MMPs in the serum, skin tissues, and wound fluid of patients are in connection with the degree of wound recovery, suggesting that MMPs can function as essential biomarkers for the diagnosis of diabetic ulcer. MMPs participate in various biological processes relevant to diabetic ulcer, such as ECM secretion, granulation tissue configuration, angiogenesis, collagen growth, re-epithelization, inflammatory response, as well as oxidative stress, thus, seeking and developing agents targeting MMPs has emerged as a potential way to treat diabetic ulcer. Natural products especially flavonoids, polysaccharides, alkaloids, polypeptides, and estrogens extracted from herbs, vegetables, as well as animals that have been extensively illustrated to treat diabetic ulcer through targeting MMPs-mediated signaling pathways, are discussed in this review and may contribute to the development of functional foods or drug candidates for diabetic ulcer therapy. This review highlights the regulation of MMPs in diabetic wound healing, and the potential therapeutic ability of natural products for diabetic wound healing by targeting MMPs.

Keywords: chronic inflammation; clinical research studies; diabetic wound healing; matrix metalloproteases; natural products.

Figure 1

Roles of MMPs in regulating inflammation-related cross-talks among keratinocytes, macrophage, and fibroblast during diabetic wound healing. (AGEs stimulates the activation of Notch-1/NICD/NF-κB, RAGE/ERK1/2, and MAPK signaling pathways in keratinocytes, which gives rise to the up-regulation of MMP-9. MMP-9 released by keratinocytes suppresses the recruitment of EPCs through down-regulating the expression of CXCL-12. In addition, TNF-α, IL-6, and other pro-inflammatory cytokines secretes by M2 macrophage elevate TIMP-1 and reduce of MMP-1, resulting in the suppressed migration of keratinocytes. Intriguingly, IL-6 also inhibits the migration as well as proliferation of fibroblast via promoting the expression of MMP-2 and MMP-9, while decreasing the levels of TIMP-2 through activating IL-6R/p38 pathway.).

Figure 2

The changes of MMPs levels in individuals with diabetic ulcers. (MMPs are influential regulators in DFUs, whose expressions are diverse in the wound fluid, skin tissue, and blood of patients. The correlations have been observed between MMPs and physiological as well as pathological processes of DFUs, involving COL deposition, inflammatory response, oxidative stress, and bacterial infection. The MMPs in red are increased in individuals with DFUs, while the MMPs in green are decreased in individuals with DFUs.).

Figure 3

Structures of natural products regulating MMPs in diabetic wound healing.

Figure 4

Regulation of MMPs by different cell types and related mechanisms. (Stimulated by HG and AGEs, keratinocytes and fibroblasts could produce a large amount of MMP-9, MMP-2, MMP-1 and MMP-14, which leads to decreased activity and migration, and ultimately causes impaired wound healing. During this process, signals such as miRNAs, lncRNAs, circRNAs, ERK1/2, FOXO1, HOXA3, Sp1, Notch, NF-κB, p38, FasL/Fas, and cells like ADSC, MSC, as well as lymphocyte are involved, which may promote or slow down the production of the above mentioned MMPs and thus affect diabetic wound healing.).