Matrix Metalloproteinases (MMPs) and Diabetic Foot: Pathophysiological Findings and Recent Developments in Their Inhibitors of Natural as well as Synthetic Origin

Abstract

Management of diabetic foot remains a major challenge for healthcare system. Though wound healing is a multiphase process and involved multiple biomarkers that acts in stepwise manner, pathophysiology diabetic foot ulcers is still not much clear and need standardization. Matrix metalloproteinases (MMPs) are often linked with non-healing characteristic of diabetic foot ulcers. They play vital roles in various phases of healing process. Major functions are removal of damaged extracellular matrix in inflammatory phase, breakdown of capillary basement membrane prior to angiogenesis and facilitation in fibroblast migration during proliferation phase. For efficient healing, these enzymes are needed in certain amount only. Imbalance of these enzymes leads to excessive degradation which has been linked with the non-healing nature of diabetic ulcers. This chapter will shed light on the role of MMP’s in various phases of wound healing and the inhibitors of MMP’s from natural as well as synthetic origin. It would help researchers and physicians to the understand nature of diabetic foot more clearly and design of strategies for diabetic foot management.

Immunology of Acute and Chronic Wound Healing

“…MMPs are normally required in a small amount and are responsible for proper epithelization and proliferation. However, their dysregulation leads to impaired epithelialization and is strongly associated with hard-to-heal wounds ( Figure 2 ) [ 111 ]. As such, an increased expression of MMP-9 by activated neutrophils is linked to delayed ulcer repair in diabetic patients [ 112 ].…”

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

“…The MMPs belong to a family of zinc-containing proteolytic enzymes that were first discovered in tadpoles with the function of the degradation of ECM ( Gross and Lapiere, 1962 ; Kaur et al, 2020 ). All MMPs share a structural similarity and several domains in common: 1) an NH 2 -terminal signal sequence (signal peptide) guiding MMPs to the secretory or plasma membrane insertion pathway; 2) a pro-peptide domain occupies the active site, blocking substrate access to the catalytic enzyme.…”

“…Developing antibody drugs as MMP inhibitors can significantly enhance the specificity and targeting of MMPs. Numerous inhibitory antibodies against MMPs have been developed, such as andecaliximab (GS-5745), a specific dual inhibitory antibody against MMP-9 ( Jones et al, 2019 ; Kaur et al, 2020 ). It inhibits MMP-9 activity in two ways: directly, by interfering with the active site of MMP-9, and indirectly, by interfering with the MMP-3 zymogen, which is involved in the activation of MMP-9 ( Sela-Passwell et al, 2011 ; Appleby et al, 2017 ).…”