PMID- 21871427 OWN - NLM STAT- MEDLINE DCOM- 20120123 LR - 20220223 IS - 1525-2191 (Electronic) IS - 0002-9440 (Print) IS - 0002-9440 (Linking) VI - 179 IP - 4 DP - 2011 Oct TI - Matrix metalloproteinase 3 is a mediator of pulmonary fibrosis. PG - 1733-45 LID - 10.1016/j.ajpath.2011.06.041 [doi] AB - Idiopathic pulmonary fibrosis (IPF) may be triggered by epithelial injury that results in aberrant production of growth factors, cytokines, and proteinases, leading to proliferation of myofibroblasts, excess deposition of collagen, and destruction of the lung architecture. The precise mechanisms and key signaling mediators responsible for this aberrant repair process remain unclear. We assessed the importance of matrix metalloproteinase-3 (MMP-3) in the pathogenesis of IPF through i) determination of MMP-3 expression in patients with IPF, ii) in vivo experiments examining the relevance of MMP-3 in experimental models of fibrosis, and iii) in vitro experiments to elucidate possible mechanisms of action. Gene expression analysis, quantitative RT-PCR, and Western blot analysis of explanted human lungs revealed enhanced expression of MMP-3 in IPF, compared with control. Transient adenoviral vector-mediated expression of recombinant MMP-3 in rat lung resulted in accumulation of myofibroblasts and pulmonary fibrosis. Conversely, MMP-3-null mice were protected against bleomycin-induced pulmonary fibrosis. In vitro treatment of cultured lung epithelial cells with purified MMP-3 resulted in activation of the beta-catenin signaling pathway, via cleavage of E-cadherin, and induction of epithelial-mesenchymal transition. These processes were inhibited in bleomycin-treated MMP-3-null mice, as assessed by cytosolic translocation of beta-catenin and cyclin D1 expression. These observations support a novel role for MMP-3 in the pathogenesis of IPF, through activation of beta-catenin signaling and induction of epithelial-mesenchymal transition. CI - Copyright (c) 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. FAU - Yamashita, Cory M AU - Yamashita CM AD - Department of Medicine, University of Western Ontario, London, Ontario, Canada. FAU - Dolgonos, Lior AU - Dolgonos L FAU - Zemans, Rachel L AU - Zemans RL FAU - Young, Scott K AU - Young SK FAU - Robertson, Jennifer AU - Robertson J FAU - Briones, Natalie AU - Briones N FAU - Suzuki, Tomoko AU - Suzuki T FAU - Campbell, Megan N AU - Campbell MN FAU - Gauldie, Jack AU - Gauldie J FAU - Radisky, Derek C AU - Radisky DC FAU - Riches, David W H AU - Riches DW FAU - Yu, Guoying AU - Yu G FAU - Kaminski, Naftali AU - Kaminski N FAU - McCulloch, Christopher A G AU - McCulloch CA FAU - Downey, Gregory P AU - Downey GP LA - eng GR - HL0894932/HL/NHLBI NIH HHS/United States GR - R01 HL090669/HL/NHLBI NIH HHS/United States GR - HL090669/HL/NHLBI NIH HHS/United States GR - CA122086/CA/NCI NIH HHS/United States GR - CA128660/CA/NCI NIH HHS/United States GR - R01 HL068628/HL/NHLBI NIH HHS/United States GR - MOP 84254/CAPMC/CIHR/Canada GR - K08 HL103772/HL/NHLBI NIH HHS/United States GR - R01 CA122086/CA/NCI NIH HHS/United States GR - HL68628/HL/NHLBI NIH HHS/United States GR - R21 CA128660/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20110824 PL - United States TA - Am J Pathol JT - The American journal of pathology JID - 0370502 RN - 0 (Cadherins) RN - 0 (RNA, Messenger) RN - 0 (Transforming Growth Factor beta) RN - 0 (beta Catenin) RN - 11056-06-7 (Bleomycin) RN - 136601-57-5 (Cyclin D1) RN - EC 3.4.24.17 (Matrix Metalloproteinase 3) RN - EC 3.4.24.24 (Matrix Metalloproteinase 2) RN - EC 3.4.24.35 (Matrix Metalloproteinase 9) SB - IM MH - Adenoviridae/genetics MH - Animals MH - Bleomycin MH - Cadherins/metabolism MH - Cyclin D1/metabolism MH - Disease Models, Animal MH - Epithelial Cells/enzymology/pathology MH - Epithelial-Mesenchymal Transition MH - Female MH - Gene Expression Regulation, Enzymologic MH - Genetic Vectors/administration & dosage MH - Humans MH - Lung/enzymology/pathology MH - Matrix Metalloproteinase 2/metabolism MH - Matrix Metalloproteinase 3/deficiency/genetics/*metabolism MH - Matrix Metalloproteinase 9/metabolism MH - Mice MH - Mice, Inbred C57BL MH - Protein Transport MH - Pulmonary Fibrosis/*enzymology/genetics/*pathology MH - RNA, Messenger/genetics/metabolism MH - Rats MH - Rats, Sprague-Dawley MH - Signal Transduction MH - Transforming Growth Factor beta/metabolism MH - beta Catenin/metabolism PMC - PMC3181358 EDAT- 2011/08/30 06:00 MHDA- 2012/01/24 06:00 PMCR- 2012/10/01 CRDT- 2011/08/30 06:00 PHST- 2010/12/08 00:00 [received] PHST- 2011/04/15 00:00 [revised] PHST- 2011/06/10 00:00 [accepted] PHST- 2011/08/30 06:00 [entrez] PHST- 2011/08/30 06:00 [pubmed] PHST- 2012/01/24 06:00 [medline] PHST- 2012/10/01 00:00 [pmc-release] AID - S0002-9440(11)00664-X [pii] AID - AJPA534 [pii] AID - 10.1016/j.ajpath.2011.06.041 [doi] PST - ppublish SO - Am J Pathol. 2011 Oct;179(4):1733-45. doi: 10.1016/j.ajpath.2011.06.041. Epub 2011 Aug 24.