Targeting Matrix Metalloproteinase-9 for Therapeutic Intervention in Diabetic Foot Ulcers

Diabetic foot ulcers (DFUs) are a complication of diabetes that have long been neglected. To date, a single drug (becaplermin containing platelet-derived growth factor, PDGF) has been approved by the FDA 27 years ago; however, it is seldom used because of its modest efficacy. The standard-of-care for DFUs is debridement, off-loading, and infection control with antibiotics, with hyperbaric oxygen (HBO) therapy being the treatment of last recourse. The paucity of understanding what accelerates diabetic wound healing results in more than 150,000 lower-limb amputations in the United States every year. A new paradigm for treatment of DFUs is proposed based on the higher levels of active matrix metalloproteinase (MMP)-9 with the more severe and infected human DFUs, and the demonstrated detrimental role of MMP-9 and the beneficial repair role of MMP-8 in diabetic mice. Selective inhibition of MMP-9 with the small molecule (R)-ND-336 lowered inflammation, reduced reactive oxygen species (ROS), and increased angiogenesis, without affecting MMP-8 to allow the natural repair mechanisms to take place. (R)-ND-336 showed better efficacy than becaplermin in diabetic mice. Becaplermin (PDGF) and HBO therapy work by decreasing MMP-9, but they do not completely suppress MMP-9 activity.