A chemical biological strategy to facilitate diabetic wound healing.
A complication of diabetes is the inability of wounds to heal in diabetic patients. Diabetic wounds are refractory to healing due to the involvement of activated matrix metalloproteinases (MMPs), which remodel the tissue resulting in apoptosis. There are no readily available methods that identify active unregulated MMPs. With the use of a novel inhibitor-tethered resin that binds exclusively to the active forms of MMPs, coupled with proteomics, we quantified MMP-8 and MMP-9 in a mouse model of diabetic wounds. Topical treatment with a selective MMP-9 inhibitor led to acceleration of wound healing, re-epithelialization, and significantly attenuated apoptosis. In contrast, selective pharmacological inhibition of MMP-8 delayed wound healing, decreased re-epithelialization, and exhibited high apoptosis. The MMP-9 activity makes the wounds refractory to healing, whereas that of MMP-8 is beneficial. The treatment of diabetic wounds with a selective MMP-9 inhibitor holds great promise in providing heretofore-unavailable opportunities for intervention of this disease.
Department of Chemistry and Biochemistry, University of Notre Dame , Notre Dame, Indiana, United States of America 46556.
Major
M
Gooyit
Zhihong
Z
Peng
William R
WR
Wolter
Hualiang
H
Pi
Derong
D
Ding
Dusan
D
Hesek
Mijoon
M
Lee
Bill
B
Boggess
Matthew M
MM
Champion
Mark A
MA
Suckow
Shahriar
S
Mobashery
Mayland
M
Chang
D000818:Animals; D048909:Diabetes Complications / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D020784:Matrix Metalloproteinase 8 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors / Q000737:chemistry / Q000627:therapeutic use*; D051379:Mice; D008958:Models, Molecular; D014945:Wound Healing / Q000187:drug effects*
D061965:Matrix Metalloproteinase Inhibitors; D020784:Matrix Metalloproteinase 8; D020780:Matrix Metalloproteinase 9