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Matrix metalloproteinase-8 overexpression prevents proper tissue repair
Patricia L Danielsen1, Anders V Holst, Henrik R Maltesen
1Department of Surgery K, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark.
Background:
The collagenolytic matrix metalloproteinase-8 (MMP-8) is essential for normal tissue repair but is often overexpressed in wounds with disrupted healing. Our aim was to study the impact of a local excess of this neutrophil-derived proteinase on wound healing using recombinant adenovirus-driven transduction of full-length Mmp8 (AdMMP-8).
Methods:
The effect of MMP-8 overexpression was evaluated in dermal fibroblasts and in two wound healing models in male Wistar rats: subcutaneously positioned ePTFE catheters and linear incisional skin wounds.
Results:
Fibroblasts transduced with AdMMP-8 secreted MMP-8 with type I collagenolytic activity that could be blocked by a selective MMP-8 inhibitor. AdMMP-8 (5 × 10(10) viral particles) administered in homologous fibrin increased MMP-8 mRNA (P < .05) levels compared to parallel wounds treated with a control adenovirus expressing lacZ (AdLacZ). Impaired wound healing was demonstrated with AdMMP-8 by decreased collagen deposition and breaking strength of incisional wounds on day 7 compared to AdLacZ-treated wounds (P < .05). We found no significant effect of AdMMP-8 on mRNA levels of MMP-9, COL1A1, or COL3A1, but AdMMP-8 treatment decreased the number of neutrophils. In the incisional wounds, MMP-8 gene transfer was not associated with significant changes in macrophage numbers or amount of granulation tissue but did increase MMP-8 protein by 76% (P < .01) and decrease type I collagen protein by 29% (P < .05) compared with AdLacZ.
Conclusion:
These results demonstrate that superphysiologic levels of the proteinase MMP-8 can result in decreased collagen and lead to impaired wound healing. This observation makes MMP-8 a potential drug target in compromised human wound healing associated with MMP-8 overexpression.
Insights
Excess matrix metalloproteinase-8 (MMP-8) impairs wound healing by reducing collagen. Targeting MMP-8 may improve healing in compromised wounds.
Area of Science:
- Biochemistry
- Wound Healing Research
- Gene Therapy
Background:
- Matrix metalloproteinase-8 (MMP-8) is crucial for tissue repair but often elevated in non-healing wounds.
- This study investigates the effects of localized MMP-8 excess on wound healing processes.
Purpose of the Study:
- To evaluate the impact of recombinant adenovirus-mediated overexpression of MMP-8 (AdMMP-8) on wound healing.
- To assess the consequences of supra-physiological MMP-8 levels in dermal fibroblasts and animal wound models.
Main Methods:
- Dermal fibroblasts and rat wound models (catheters, skin incisions) were used.
- AdMMP-8 was administered to induce MMP-8 overexpression, with AdLacZ as a control.
- Collagen deposition, breaking strength, and protein/gene expression levels were analyzed.
Main Results:
- AdMMP-8 treatment led to increased MMP-8 mRNA and protein levels.
- Impaired wound healing was observed, characterized by reduced collagen deposition and lower breaking strength.
- Neutrophil counts decreased, while MMP-8 protein increased significantly and type I collagen protein decreased.
Conclusions:
- Super-physiological levels of MMP-8 negatively impact collagen levels and impair wound healing.
- MMP-8 presents a potential therapeutic target for managing human wound healing complications associated with its overexpression.
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