Regulation of MMP-2 gene transcription in dermal wounds.
Matrix metalloproteinase-2 (MMP-2, gelatinase A) plays an essential role in angiogenesis, inflammation, and fibrosis. These processes are critical for wound healing and accordingly elevated levels of MMP-2 expression have been detected after skin injury. Our goal was to investigate the transcriptional activation of the MMP-2 gene in a model of skin injury by using two different MMP-2/LacZ-reporter mice. Upon skin injury MMP-2 expression was upregulated, whereas tissue from normal skin stained negative except for occasional macrophages, sweat glands, and hair follicles. Skin injury also activated MMP-2 proteolytic activity and reporter gene expression. We demonstrate that MMP-2 regulatory sequences -1686/+423 drive appropriate injury-induced MMP-2-promoter activation. Reporter gene expression was predominantly detectable in endothelial cells and in macrophages. Deletion of the 5' responsive element, denoted RE-1, residing at -1241/+423 bp of the regulatory sequence led to abrogated MMP-2 transcription in vivo. The findings define a crucial role for the enhancer element RE-1 in injury-induced MMP-2 transcription of the skin.
Jansen
Petra Lynen
PL
Interdisciplinary Centre for Clinical Research BIOMAT, University Hospital, RWTH Aachen, Aachen, Germany. plynen@ukaachen.de
Rosch
Raphael
R
Jansen
Marc
M
Binnebösel
Marcel
M
Junge
Karsten
K
Alfonso-Jaume
Alexandra
A
Klinge
Uwe
U
Lovett
David H
DH
Mertens
Peter R
PR
D000818:Animals; D042783:Endothelial Cells / Q000502:physiology; D004742:Enhancer Elements, Genetic / Q000235:genetics / Q000502:physiology; D005355:Fibrosis / Q000235:genetics / Q000503:physiopathology; D008264:Macrophages / Q000502:physiology; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D018919:Neovascularization, Physiologic / Q000235:genetics / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000235:genetics / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics / Q000502:physiology*; D012867:Skin / Q000293:injuries* / Q000503:physiopathology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic / Q000502:physiology*; D014945:Wound Healing / Q000235:genetics / Q000502:physiology*; D000099229:RE1-Silencing Transcription Factor
D020778:Matrix Metalloproteinase 2; D012097:Repressor Proteins; D014157:Transcription Factors; D000099229:RE1-Silencing Transcription Factor