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Published on: March 25, 2020
Matrix metalloproteinase-9 delays wound healing in a murine wound model
Matthew J Reiss1, Yan-Ping Han, Edwin Garcia
1Division of Plastic Surgery, University of Southern California, Los Angeles, CA, USA.
Background:
Metalloproteinase-9 (MMP-9) is a type IV collagenase found at elevated levels in chronic wounds. As wounds heal, MMP-9 diminishes. In this study, we investigated whether MMP-9 directly contributes to chronic wound pathogenesis.
Methods:
Recombinant proMMP-9 was prepared using immortalized keratinocytes transduced by a lentivirus. ProMMP-9 was purified from cell culture media and activated using 4-aminophenylmercuric acetate. Active MMP-9 was then suspended in xanthan gum to a concentration paralleling that found in human chronic wounds. Two parallel 6-mm punch biopsies were made on the backs of C57BL mice. Wounds were treated daily with MMP-9 or vehicle. Wound areas were measured and tissues examined by densitometry, real-time RT-PCR, histology, and immunohistochemistry at days 7, 10, and 12.
Results:
Exogenous MMP-9, at the level found within chronic wounds, delayed wound healing in this animal model. By 7 days, wounds in the MMP-9-injected group were 12% larger than control wounds (P = .008). By day 12, wounds in the MMP-9-injected group were 25% larger than those of the control group (P = .03). Histologic examination shows that high levels of active MMP-9-impaired epithelial migrating tongues (P = .0008). Moreover, consistent with elevated MMP-9, the collagen IV in the leading edge of the epithelial tongue was diminished.
Conclusion:
MMP-9 appears to directly delay wound healing. Our data suggests that this may occur through interference with re-epithelialization. We propose that MMP-9 interferes with the basement membrane protein structure, which in turn impedes keratinocyte migration, attachment, and the reestablishment of the epidermis.
Insights
Elevated levels of matrix metalloproteinase-9 (MMP-9) directly delay chronic wound healing. This occurs by impairing epithelialization and disrupting the basement membrane structure essential for skin repair.
Area of Science:
- Wound healing research
- Biochemistry
- Dermatology
Background:
- Matrix metalloproteinase-9 (MMP-9) is elevated in chronic wounds.
- MMP-9 levels typically decrease as wounds heal.
- This study investigates MMP-9's direct role in chronic wound pathogenesis.
Purpose of the Study:
- To determine if MMP-9 directly contributes to chronic wound development.
- To elucidate the mechanism by which MMP-9 may impede wound closure.
Main Methods:
- Recombinant proMMP-9 was produced, purified, and activated.
- Active MMP-9 was applied to mouse wound models at chronic wound concentrations.
- Wound healing was assessed via area measurements and histological/molecular analyses.
Main Results:
- Exogenous MMP-9 significantly delayed wound closure in mice.
- MMP-9 treated wounds were larger by 12% at day 7 and 25% by day 12.
- Histology revealed impaired epithelial tongues and reduced collagen IV in MMP-9 treated wounds.
Conclusions:
- MMP-9 directly delays wound healing.
- This delay is likely due to interference with re-epithelialization.
- MMP-9 disrupts basement membrane structure, impeding keratinocyte migration and epidermal reestablishment.
