Polymeric meshes induce zonal regulation of matrix metalloproteinase-2 gene expression by macrophages and fibroblasts

Interdisciplinary Center for Clinical Research BIOMAT, University Hospital, Pauwelsstr. 30, 52074 Aachen, Germany.
The FASEB Journal (Impact Factor: 5.04). 05/2007; 21(4):1047-57. DOI: 10.1096/fj.06-6755com
Source: PubMed


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.

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    • "These include activating protein-2 (AP 2) [37], Y-box protein-1 (YB-1) [38], signal transduction and activator of transcription factor 3 (Stat3) [41], and p53 [36]. In a previously published study by Jansen et al. it could be shown that macrophages that are adjacent to the mesh filaments play a crucial role for mesh induced MMP-2 expression [9]. Therefore, the gentamicin mediated down-regulation of MMP-2 transcription in our study might be due to a cellular effect, e.g. by reducing infiltration or activation of macrophages or other inflammatory cells that are involved in MMP-2 expression. "
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