Polymeric meshes induce zonal regulation of matrix metalloproteinase-2 gene expression by macrophages and fibroblasts.
Matrix metalloproteinase-2 (MMP-2) is a key regulator in wound healing that orchestrates tissue remodeling. In the present study the spatial and temporal distribution of MMP-2 gene transcription, protein synthesis, and enzymatic activity were analyzed following polymeric mesh (polyglactin, polypropylene) implantation in transgenic reporter mice harboring MMP-2 regulatory sequences -1686/+423 or -1241/+423. Polymers induced MMP-2 promoter activity in macrophages within the foreign body granuloma via sequences -1686/+423 with concomitantly up-regulated protein synthesis and enzymatic activity. Macrophages distant from mesh filaments exhibited low MMP-2 expression levels. Fibroblasts surrounding mesh material displayed strong MMP-2 gene transcription independent of the included promoter sequences, whereas fibroblasts without close contact to mesh material had low MMP-2 synthesis rates due to silencing activity of sequences -1686/-1241. In vitro studies support a cellular crosstalk concept, as macrophages trans-repressed MMP-2 gene transcription in fibroblasts. The zonal and cell-specific regulation of MMP-2 gene transcription illuminates an intimate cellular crosstalk in foreign body reaction that may provide a new approach for mesh modification.
Jansen
Petra Lynen
PL
Interdisciplinary Center for Clinical Research BIOMAT, University Hospital, Pauwelsstr. 30, 52074 Aachen, Germany. plynen@ukaachen.de
Kever
Mona
M
Rosch
Raphael
R
Krott
Ellen
E
Jansen
Marc
M
Alfonso-Jaume
Alexandra
A
Dooley
Steven
S
Klinge
Uwe
U
Lovett
David H
DH
Mertens
Peter R
PR
D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry; D005347:Fibroblasts / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D006099:Granuloma / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D041681:NIH 3T3 Cells; D011108:Polymers / Q000737:chemistry*; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic; D014945:Wound Healing
D001672:Biocompatible Materials; D011108:Polymers; D020778:Matrix Metalloproteinase 2