title: Matrix metalloproteinase-8 overexpression prevents proper tissue repair.
abstract: 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Surgery K, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Danielsen
authors.forename: Anders V
authors.initials: AV
authors.lastname: Holst
authors.forename: Henrik R
authors.initials: HR
authors.lastname: Maltesen
authors.forename: Maria R
authors.initials: MR
authors.lastname: Bassi
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Holst
authors.forename: Katja M
authors.initials: KM
authors.lastname: Heinemeier
authors.forename: Jørgen
authors.initials: J
authors.lastname: Olsen
authors.forename: Carl C
authors.initials: CC
authors.lastname: Danielsen
authors.forename: Steen S
authors.initials: SS
authors.lastname: Poulsen
authors.forename: Lars N
authors.initials: LN
authors.lastname: Jorgensen
authors.forename: Magnus S
authors.initials: MS
authors.lastname: Agren
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D020405:Dermis / Q000293:injuries* / Q000473:pathology / Q000502:physiology; D004195:Disease Models, Animal; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology*; D015971:Gene Expression Regulation, Enzymologic / Q000235:genetics; D006097:Granulation Tissue / Q000502:physiology; D008264:Macrophages / Q000473:pathology; D008297:Male; D020784:Matrix Metalloproteinase 8 / Q000235:genetics* / Q000378:metabolism*; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D014945:Wound Healing / Q000502:physiology*
chemical_list: D003094:Collagen; D020784:Matrix Metalloproteinase 8