Nonhealing chronic
wounds are major complications of diabetes resulting in >70,000 annual lower-limb
amputations in the United States alone. The reasons the diabetic
wound is recalcitrant to healing are not fully understood, and there are limited therapeutic agents that could accelerate or facilitate its repair. We previously identified two active forms of
matrix metalloproteinases (
MMPs), MMP-8 and MMP-9, in the
wounds of db/db mice. We argued that the former might play a role in the body's response to wound healing and that the latter is the pathological consequence of the disease with detrimental effects. Here we demonstrate that the use of compound ND-336, a novel highly selective inhibitor of
gelatinases (MMP-2 and MMP-9) and MMP-14, accelerates diabetic wound healing by lowering
inflammation and by enhancing angiogenesis and re-epithelialization of the
wound, thereby reversing the pathological condition. The detrimental role of MMP-9 in the pathology of diabetic
wounds was confirmed further by the study of diabetic MMP-9-knockout mice, which exhibited
wounds more prone to healing. Furthermore,
topical administration of active recombinant MMP-8 also accelerated diabetic wound healing as a consequence of complete re-epithelialization, diminished
inflammation, and enhanced angiogenesis. The combined topical application of ND-336 (a small molecule) and the active recombinant MMP-8 (an
enzyme) enhanced healing even more, in a strategy that holds considerable promise in healing of diabetic
wounds.