Patterns of matrix metalloproteinase and TIMP expression in chronic ulcers

Controlled proteolysis is needed for cell migration, angiogenesis, and matrix remodeling during normal wound repair. Our objective has been to investigate how chronic leg ulcers differ from normally healing wounds (pinch graft donor sites) with respect to their metalloproteinase expression patterns. Using in situ hybridization and immunohistochemistry, we found that collagenase-1 (MMP-1), stromelysin-1 (MMP-3) and stromelysin-2 (MMP-10) were expressed in keratinocytes bordering both acute and chronic wounds. Unlike MMP-1, signal for collagenase-3 (MMP-13) was not detected in keratinocytes but exclusively in fibroblasts deep in the ulcer bed of chronic wounds, suggesting that while MMP-1 production is important for migration, MMP-13 plays a role in matrix remodeling. Tissue inhibitor of metalloproteinase (TIMP)-1 was not detected in the epidermis of any chronic wound sample while it was expressed in keratinocytes bordering normally healing wounds. TIMP-3 was abundantly expressed in stromal fibroblast- and macrophage-like cells surrounding vessels and sweat glands in both types of wounds. Our results suggest that there are no qualitative differences in the expression of MMPs-1, -3 and -10 in the epidermis of chronic vs normally healing wounds. However, the number of stromal cells expressing MMP-1 and MMP-3 was greater in chronic vs acute wounds, whereas MMP-10 was never detected in the dermis. TIMP-1 expression near the basement membrane in acute, but not in chronic, wounds suggests that the balance between MMPs and their inhibitors may be altered in poorly healing wounds. Analogous to chronic cutaneous wounds, MMP-1 and -3 are abundantly expressed in chronic small and large bowel ulcers, while the migrating surface epithelium is negative for TIMP-1 expression.