Polymeric meshes induce zonal regulation of matrix metalloproteinase-2 gene expression by macrophages and fibroblasts Petra Lynen Jansen * ,1 , Mona Kever † , Raphael Rosch † , Ellen Krott † , Marc Jansen † , Alexandra Alfonso-Jaume ‡ , Steven Dooley § , Uwe Klinge † , David H. Lovett || and Peter R. Mertens ¶ * Interdisciplinary Center for Clinical Research BIOMAT, Aachen, Germany; † Department of Surgery, University Hospital, RWTH Aachen, Germany; ‡ Department of Medicine, Williams Middleton Memorial, University of Wisconsin, Madison, Wisconsin, USA; § Department of Medicine II, University Hospital, Mannheim, Germany; || Department of Medicine, San Francisco Veterans Affairs Medical Center, University of California, San Francisco, California, USA; and ¶ Department of Nephrology and Clinical Immunology, University Hospital, Aachen, Germany 1 Correspondence: Interdisciplinary Center for Clinical Research BIOMAT, University Hospital, Pauwelsstr. 30, 52074 Aachen, Germany. E-mail: plynen@ukaachen.de 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, P. L., Kever, M., Rosch, R., Krott, E., Jansen, M., Alfonso-Jaume, A., Dooley, S., Klinge, U., Lovett, D. H., Mertens, P. R. Polymeric meshes induce zonal regulation of matrix metalloproteinase-2 gene expression by macrophages and fibroblasts. Key Words: polymers • wound healing • cell-specific gene regulation • transgene
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Polymeric meshes induce zonal regulation of matrix metalloproteinase-2 gene expression by macrophages and fibroblasts
Jansen, Petra Lynen; Kever, Mona; Rosch, Raphael; Krott, Ellen; Jansen, Marc; Alfonso-Jaume, Alexandra; Dooley, Steven; Klinge, Uwe; Lovett, David H.; Mertens, Peter R.
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, Volume 21 (4): 1047
Fed of American Socs for Experimental Biology – Apr 1, 2007
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