Abstract
Diabetic foot ulcers (DFUs) are significant complications of diabetes and an unmet medical need. Matrix metalloproteinases (MMPs) play important roles in the pathology of wounds and in the wound healing process. However, because of the challenge in distinguishing active MMPs from the two catalytically inactive forms of MMPs and the clinical failure of broad-spectrum MMP inhibitors in cancer, MMPs have not been a target for treatment of DFUs until recently. This review covers the discovery of active MMP-9 as the biochemical culprit in the recalcitrance of diabetic wounds to healing and targeting this proteinase as a novel approach for the treatment of DFUs. Active MMP-8 and MMP-9 were observed in mouse and human diabetic wounds using a batimastat affinity resin and proteomics. MMP-9 was shown to play a detrimental role in diabetic wound healing, whereas MMP-8 was beneficial. A new class of selective MMP-9 inhibitors shows clinical promise for the treatment of DFUs.
Highlights
The skin, one of the largest human organs, is responsible for three critical roles: protection from the environment, maintaining homeostasis, and sensing the surroundings
As Matrix metalloproteinases (MMPs)-9 has long been of interest in wound healing, most studies have focused on the effects on this proteinase in particular [42]
A small-scale study showed a reduction in MMP-9 and MMP-2 by gelatin zymography in chronic wounds of human patients treated with Vacuum-assisted closure (VAC), though the small number of subjects precludes any meaningful statistics [43]
Summary
The skin, one of the largest human organs, is responsible for three critical roles: protection from the environment, maintaining homeostasis, and sensing the surroundings. Indiscriminate inhibition of all MMPs resulted in inundesirable undesirableside sideeffects, effects, such such as as musculoskeletal musculoskeletal pain pain and and inflammation inflammationobserved observedduring duringphase phaseI I clinical studies [22]. Many MMPs have been identified in chronic wounds: MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-12, MMP-13, and MMP-14 [31,40] These MMPs were identified using methods that do not distinguish among the three forms of MMPs. Only active MMPs in the absence of regulation by TIMPs are catalytically competent to play roles in the pathology of chronic wounds. Given the failure of MMPIs for treatment of cancer, it is important to have a solid understanding of what roles are played by which active unregulated MMP(s)
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