Matrix metalloproteinase 3 is a mediator of pulmonary fibrosis

Cory M. Yamashita, Lior Dolgonos, Rachel L. Zemans, Scott K. Young, Jennifer Robertson, Natalie Briones, Tomoko Suzuki, Megan N. Campbell, Jack Gauldie, Derek C Radisky, David W H Riches, Guoying Yu, Naftali Kaminski, Christopher A G McCulloch, Gregory P. Downey

Research output: Contribution to journalArticle

91 Citations (Scopus)

Abstract

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 β-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 β-catenin and cyclin D1 expression. These observations support a novel role for MMP-3 in the pathogenesis of IPF, through activation of β-catenin signaling and induction of epithelial-mesenchymal transition.

Original languageEnglish (US)
Pages (from-to)1733-1745
Number of pages13
JournalAmerican Journal of Pathology
Volume179
Issue number4
DOIs
StatePublished - Oct 2011

Fingerprint

Matrix Metalloproteinase 3
Pulmonary Fibrosis
Idiopathic Pulmonary Fibrosis
Catenins
Lung
Epithelial-Mesenchymal Transition
Myofibroblasts
Cyclin D1
Bleomycin
Cadherins
Intercellular Signaling Peptides and Proteins
Fibrosis
Peptide Hydrolases
Theoretical Models
Collagen
Western Blotting
Epithelial Cells
Cytokines
Gene Expression
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Yamashita, C. M., Dolgonos, L., Zemans, R. L., Young, S. K., Robertson, J., Briones, N., ... Downey, G. P. (2011). Matrix metalloproteinase 3 is a mediator of pulmonary fibrosis. American Journal of Pathology, 179(4), 1733-1745. https://doi.org/10.1016/j.ajpath.2011.06.041

Matrix metalloproteinase 3 is a mediator of pulmonary fibrosis. / Yamashita, Cory M.; Dolgonos, Lior; Zemans, Rachel L.; Young, Scott K.; Robertson, Jennifer; Briones, Natalie; Suzuki, Tomoko; Campbell, Megan N.; Gauldie, Jack; Radisky, Derek C; Riches, David W H; Yu, Guoying; Kaminski, Naftali; McCulloch, Christopher A G; Downey, Gregory P.

In: American Journal of Pathology, Vol. 179, No. 4, 10.2011, p. 1733-1745.

Research output: Contribution to journalArticle

Yamashita, CM, Dolgonos, L, Zemans, RL, Young, SK, Robertson, J, Briones, N, Suzuki, T, Campbell, MN, Gauldie, J, Radisky, DC, Riches, DWH, Yu, G, Kaminski, N, McCulloch, CAG & Downey, GP 2011, 'Matrix metalloproteinase 3 is a mediator of pulmonary fibrosis', American Journal of Pathology, vol. 179, no. 4, pp. 1733-1745. https://doi.org/10.1016/j.ajpath.2011.06.041
Yamashita CM, Dolgonos L, Zemans RL, Young SK, Robertson J, Briones N et al. Matrix metalloproteinase 3 is a mediator of pulmonary fibrosis. American Journal of Pathology. 2011 Oct;179(4):1733-1745. https://doi.org/10.1016/j.ajpath.2011.06.041
Yamashita, Cory M. ; Dolgonos, Lior ; Zemans, Rachel L. ; Young, Scott K. ; Robertson, Jennifer ; Briones, Natalie ; Suzuki, Tomoko ; Campbell, Megan N. ; Gauldie, Jack ; Radisky, Derek C ; Riches, David W H ; Yu, Guoying ; Kaminski, Naftali ; McCulloch, Christopher A G ; Downey, Gregory P. / Matrix metalloproteinase 3 is a mediator of pulmonary fibrosis. In: American Journal of Pathology. 2011 ; Vol. 179, No. 4. pp. 1733-1745.
@article{87c0d3387808466ab59cfdfa173eb965,
title = "Matrix metalloproteinase 3 is a mediator of pulmonary fibrosis",
abstract = "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 β-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 β-catenin and cyclin D1 expression. These observations support a novel role for MMP-3 in the pathogenesis of IPF, through activation of β-catenin signaling and induction of epithelial-mesenchymal transition.",
author = "Yamashita, {Cory M.} and Lior Dolgonos and Zemans, {Rachel L.} and Young, {Scott K.} and Jennifer Robertson and Natalie Briones and Tomoko Suzuki and Campbell, {Megan N.} and Jack Gauldie and Radisky, {Derek C} and Riches, {David W H} and Guoying Yu and Naftali Kaminski and McCulloch, {Christopher A G} and Downey, {Gregory P.}",
year = "2011",
month = "10",
doi = "10.1016/j.ajpath.2011.06.041",
language = "English (US)",
volume = "179",
pages = "1733--1745",
journal = "American Journal of Pathology",
issn = "0002-9440",
publisher = "Elsevier Inc.",
number = "4",

}

TY - JOUR

T1 - Matrix metalloproteinase 3 is a mediator of pulmonary fibrosis

AU - Yamashita, Cory M.

AU - Dolgonos, Lior

AU - Zemans, Rachel L.

AU - Young, Scott K.

AU - Robertson, Jennifer

AU - Briones, Natalie

AU - Suzuki, Tomoko

AU - Campbell, Megan N.

AU - Gauldie, Jack

AU - Radisky, Derek C

AU - Riches, David W H

AU - Yu, Guoying

AU - Kaminski, Naftali

AU - McCulloch, Christopher A G

AU - Downey, Gregory P.

PY - 2011/10

Y1 - 2011/10

N2 - 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 β-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 β-catenin and cyclin D1 expression. These observations support a novel role for MMP-3 in the pathogenesis of IPF, through activation of β-catenin signaling and induction of epithelial-mesenchymal transition.

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 β-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 β-catenin and cyclin D1 expression. These observations support a novel role for MMP-3 in the pathogenesis of IPF, through activation of β-catenin signaling and induction of epithelial-mesenchymal transition.

UR - http://www.scopus.com/inward/record.url?scp=80053272507&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=80053272507&partnerID=8YFLogxK

U2 - 10.1016/j.ajpath.2011.06.041

DO - 10.1016/j.ajpath.2011.06.041

M3 - Article

C2 - 21871427

AN - SCOPUS:80053272507

VL - 179

SP - 1733

EP - 1745

JO - American Journal of Pathology

JF - American Journal of Pathology

SN - 0002-9440

IS - 4

ER -