title: Acceleration of diabetic wound healing using a novel protease-anti-protease combination therapy.
abstract: 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.
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556;
authors.forename: Ming
authors.initials: M
authors.lastname: Gao
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556;
authors.forename: Trung T
authors.initials: TT
authors.lastname: Nguyen
authors.affiliation: Freimann Life Sciences Center, University of Notre Dame, Notre Dame, IN 46556, Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Suckow
authors.affiliation: Freimann Life Sciences Center, University of Notre Dame, Notre Dame, IN 46556, Department of Biological Sciences, University of Notre Dame, Notre Dame, IN 46556.
authors.forename: William R
authors.initials: WR
authors.lastname: Wolter
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556;
authors.forename: Major
authors.initials: M
authors.lastname: Gooyit
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556;
authors.forename: Shahriar
authors.initials: S
authors.lastname: Mobashery
authors.affiliation: Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN 46556; mchang@nd.edu.
authors.forename: Mayland
authors.initials: M
authors.lastname: Chang
mesh_terms: D000818:Animals; D048909:Diabetes Complications; D020784:Matrix Metalloproteinase 8 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D011480:Protease Inhibitors / Q000494:pharmacology*; D014945:Wound Healing / Q000187:drug effects*; D014947:Wounds and Injuries / Q000201:enzymology
chemical_list: D011480:Protease Inhibitors; D020784:Matrix Metalloproteinase 8; D020780:Matrix Metalloproteinase 9
keywords: MMP-8; MMP-9; ND-336; diabetic wound healing; inhibition