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.