title: Polymeric meshes induce zonal regulation of matrix metalloproteinase-2 gene expression by macrophages and fibroblasts.
abstract: 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.
authors.affiliation: Interdisciplinary Center for Clinical Research BIOMAT, University Hospital, Pauwelsstr. 30, 52074 Aachen, Germany. plynen@ukaachen.de
authors.forename: Petra Lynen
authors.initials: PL
authors.lastname: Jansen
authors.forename: Mona
authors.initials: M
authors.lastname: Kever
authors.forename: Raphael
authors.initials: R
authors.lastname: Rosch
authors.forename: Ellen
authors.initials: E
authors.lastname: Krott
authors.forename: Marc
authors.initials: M
authors.lastname: Jansen
authors.forename: Alexandra
authors.initials: A
authors.lastname: Alfonso-Jaume
authors.forename: Steven
authors.initials: S
authors.lastname: Dooley
authors.forename: Uwe
authors.initials: U
authors.lastname: Klinge
authors.forename: David H
authors.initials: DH
authors.lastname: Lovett
authors.forename: Peter R
authors.initials: PR
authors.lastname: Mertens
mesh_terms: 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
chemical_list: D001672:Biocompatible Materials; D011108:Polymers; D020778:Matrix Metalloproteinase 2