Mechanisms of diabetic foot ulceration: A review

Abstract

Diabetic foot ulcers (DFUs) are associated with complex pathogenic factors and are considered a serious complication of diabetes. The potential mechanisms underlying DFUs have been increasingly investigated. Previous studies have focused on the three aspects of diabetic peripheral vascular disease, neuropathy, and wound infections. With advances in technology, researchers have been gradually conducting studies using immune cells, endothelial cells, keratinocytes, and fibroblasts, as they are involved in wound healing. It has been reported that the upregulation or downregulation of molecular signaling pathways is essential for the healing of DFUs. With a recent increase in the awareness of epigenetics, its regulatory role in wound healing has become a much sought-after trend in the treatment of DFUs. This review focuses on four aspects involved in the pathogenesis of DFUs: physiological and pathological mechanisms, cellular mechanisms, molecular signaling pathway mechanisms, and epigenetics. Given the challenge in the treatment of DFUs, we are hopeful that our review will provide new ideas for peers.

Keywords: diabetic foot ulcer; epigenetics; physiology and pathology; signaling pathway; wound healing; 信号通路; 创面愈合; 生理病理; 糖尿病足溃疡; 表观遗传学.

FIGURE 1

The four main aspects of diabetic foot ulcer formation: peripheral arterial disease, peripheral neuropathy, bacterial infection, and cell dysfunction. (A) Peripheral arterial disease is the most important factor in the development of diabetic foot. Severe ischemia of the skin of the lower extremities leads to ulcerated tissues becoming necrotic due to insufficient blood supply. (B) Peripheral neuropathy leads to sensory, motor, and secretory dysfunctions in the skin of the lower extremities. These pathological changes not only alter the physical mechanics of the feet and lead to a loss of protective sensation (direct factors in the formation of ulcer wounds) but also cause dry skin, which is not conducive to the healing of diabetic wounds. (C) Infection of wounds by bacteria further delays healing. Because of a reduction in beneficial inflammatory factors and an increase in harmful inflammatory factors, normal wound healing is delayed. (D) The functional status of wound cells directly determines healing quality. The special microenvironment of diabetic wounds is not conducive to the execution of normal cell functions. For example, in the inflammatory phase, there is an imbalance between the proinflammatory and anti‐inflammatory effects of macrophages and neutrophils. In the proliferation stage, the proliferation and migration of endothelial cells are impaired. In the remodeling stage, fibroblasts differentiate and secrete collagen abnormally. In addition, dysfunction in keratinocyte proliferation and differentiation is observed.

FIGURE 2

The process of wound healing generally needs to go through the stages of coagulation, inflammation, proliferation and remodeling. Different cells are involved in each stage. In addition, cells at different stages secrete a variety of cytokines to speed up the healing process. CCN‐1, cellular communication network factor‐1; DFU, diabetic foot ulcer; ECM, extracellular matrix; EGF, epidermal growth factor; FGF, fibroblast cytokine; ICAM, intracellular adhesion molecule; IL, interleukin; iNOS, inducible nitric oxide synthase; MCP‐1, monocyte chemoattractant protein‐1; MMP‐9, matrix metalloproteinase‐9; NET, neutrophil extracellular trap; NGAL, neutrophil gelatinase‐associated lipocalin; PDGF, platelet‐derived growth factor; TGF‐ β1, transforming growth factor beta‐1; VCAM, vascular cell adhesion molecule; VEGF, vascular endothelial growth factor.

FIGURE 3

Regulatory role of several key signaling pathways in wound healing. Activation of the Wnt/β‐catenin signaling pathway can promote cell proliferation, migration, and differentiation. Activation of the phosphatidylinositol‐3‐kinas (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway stimulates cell proliferation, migration, and differentiation, and inhibits autophagy. It also affects the function of Wnt/β‐catenin through phosphorylated Akt. This pathway can be inhibited by PTEN. Activation of the Notch signaling pathway can promote cell proliferation and migration. Activation of the Janus kinase and signal transducer and activator of transcription (JAK–STAT) signaling pathway can promote cell differentiation and inhibit autophagy, and phosphorylated STAT can enhance the activation of PI3K and inhibit the function of NF‐κB. However, this signaling pathway can be inhibited by suppressor of cytokine signaling (SOCS). The NF‐κB signaling pathway can promote cell proliferation and inhibit autophagy. AKT, protein kinase B; APC, adenomatous polyposis coli; CK1, casein kinase 1; CSL, C‐promoter binding factor‐1; GFAP, glial fibrillary acidic protein; GSK3β, glycogen synthase kinase‐3 beta; LEF, lymphoid enhancer binding factor; NF‐κB, nuclear factor‐κB; NICD, Notch intracellular domain; PKD, protein kinase D; PPARγ, proliferator‐activated receptor gamma; SREBP, sterol regulatory element‐binding protein; TCF, T cell factor.