Expression and activation of matrix metalloproteinases in wounds: Modulation by the tripeptide-copper complex glycyl-L-histidyl-L-lysine-Cu2+

We investigated the expression and activation of matrix metalloproteinases in a model of experimental wounds in rats, and their modulation by glycyl-L -histidyl-L-lysine-Cu(II), a potent activator of wound repair. Wound chambe rs were inserted under the skin of Sprague-Dawley rats and received serial injections of either 2 mg glycyl-L-histidyl-L-lysine-Cu(II) or the same vol ume of saline. The wound fluid and the neosynthetized connective tissue dep osited in the chambers were collected and analyzed for matrix metalloprotei nase expression and/or activity, Interstitial collagenase increased progres sively in the wound fluid throughout the experiment, Glycyl-L-histidyl-L-ly sine-Cu(TI) treatment did not alter its activity. Matrix metalloproteinase- 9 (gelatinase B) and matrix metalloproteinase-2 (gelatinase A) were the two main gelatinolytic activities expressed during the healing process. Pro-ma trix metalloproteinase (pro-form of matrix metalloproteinase)-9 was strongl y expressed during the early stages of wound healing (day 3), In the wound fluid, it decreased rapidly and disappeared after day 18, whereas in the wo und tissue, matrix metalloproteinase-9 expression persisted in the glycyl-L -histidyl-L-lysine-Cu(II) injected chamber until day 22, Pro-matrix metallo proteinase-2 was expressed at low levels at the beginning of the healing pr ocess, increased progressively until day 7, then decreased until day 18, Ac tivated matrix metalloproteinase-2 was present in wound fluid and wound tis sue. It increased until day 12, then decreased progressively. Glycyl-L-hist idyl-L-lysine-Cu(II) injections increased pro-matrix metalloproteinase-2 an d activated matrix metalloproteinase-2 during the later stages of healing ( days 18 and/or 22), These results demonstrate that various types of matrix metalloproteinases are selectively expressed or activated at the various pe riods of wound healing. Glycyl-L-histidyl-L-lysine-Cu(II) is able to modula te their expression and might significantly alter wound remodeling.