Mitogenic bovine whey extract modulates matrix metalloproteinase‐2, ‐9, and tissue inhibitor of matrix metalloproteinase‐2 levels in chronic leg ulcers

Abstract

ABSTRACTMatrix metalloproteinases (MMPs) and their tissue inhibitors play important roles in the wound‐healing process. An imbalance in the expression of these molecules is thought to contribute to the failure of chronic ulcers to heal. We investigated whether a mitogenic bovine whey extract enriched with growth factors modulated the expression and activity of MMP‐2 and ‐9, and the tissue inhibitor of MMP‐2 (TIMP‐2) in chronic leg ulcers. Wound fluids and biopsies were collected from chronic leg ulcer patients whose ulcers were treated topically for 4 weeks with placebo or mitogenic bovine whey extract at concentrations of 2.5, 10, and 20 mg/mL. The levels of MMP‐2 and ‐9 in wound fluid samples was assessed by gelatin zymography and showed a decrease in active MMP‐2 in the 2.5 and 10.0 mg/mL mitogenic bovine whey extract‐treated ulcers compared with placebo (p<0.05). Immunohistochemical analysis of ulcer biopsies for MMP‐2, ‐9, and TIMP‐2 expression showed a reduction in the number of MMP‐2–positive dermal fibroblasts in the mitogenic bovine whey extract‐treated ulcers compared with pretreatment biopsies (p<0.05) that persisted over the course of the study. In contrast, a transient increase in the number of MMP‐9– and TIMP‐2–positive cells was observed in mitogenic bovine whey extract treated ulcer biopsies compared with pretreatment levels (p<0.05). These results show that topical application of mitogenic bovine whey extract was able to modulate the expression of MMP‐2, ‐9, and TIMP‐2 in chronic leg ulcers and that its constituent growth factors may have the potential to redress the proteolytic imbalance observed in nonhealing chronic ulcers.