Restructuring of the extracellular matrix in diabetic wounds and healing: A perspective

Pharmacol Res. 2016 May:107:243-248. doi: 10.1016/j.phrs.2016.03.008. Epub 2016 Mar 24.


Diabetic foot ulcers are a complication of diabetes for which treatment options are limited and not effective, resulting in 73,000 lower-limb amputations in the United States every year. Wound healing is a complex process with a highly orchestrated cascade of events, in which the extracellular matrix (ECM) interacts with growth factors and cells. Matrix metalloproteinases (MMPs) are involved in all wound healing events, in particular MMP-8 and MMP-9, whose physiological functions are to degrade damaged collagen type I and to facilitate keratinocyte migration and re-epithelialization, respectively. MMP substrate redundancy permits another MMP to substitute for MMP-9 during normal wound healing. Under the hypoxic and inflammatory environment of diabetic wounds, increased reactive oxygen species (ROS) and upregulation of MMP-9 results in wounds that are recalcitrant to healing. We have determined that MMP-8 plays a role in the body's response to wound healing and that MMP-9 is the pathological consequence of the disease with detrimental effects. Thus, selective inhibition of MMP-9, while leaving MMP-8 activity unaffected, is desirable. ND-336 has such inhibitory profile and is a promising strategy for treatment of diabetic foot ulcers.

Keywords: Diabetic wounds; Extracellular matrix; MMP-8; MMP-9; ND-336.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Diabetes Complications / drug therapy*
  • Extracellular Matrix / drug effects
  • Humans
  • Matrix Metalloproteinase 9 / metabolism
  • Matrix Metalloproteinase Inhibitors / pharmacology
  • Matrix Metalloproteinase Inhibitors / therapeutic use*
  • Wound Healing / drug effects*


  • Matrix Metalloproteinase Inhibitors
  • Matrix Metalloproteinase 9