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J Biol Chem. 2017 Jun 23;292(25):10490-10519. doi: 10.1074/jbc.M116.752469. Epub 2017 Apr 7.

Transforming growth factor β1 (TGFβ1)-induced CD44V6-NOX4 signaling in pathogenesis of idiopathic pulmonary fibrosis.

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From the Department of Regenerative Medicine and Cell Biology,
the Department of Biomedical Engineering/ND20, Cleveland Clinic, Cleveland, Ohio 44195.
From the Department of Regenerative Medicine and Cell Biology.
the Division of Rheumatology and Immunology, Department of Medicine, and.
the Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129.
the College of Pharmacy/Pharmaceutical Biomedical Science, Medical University of South Carolina, Charleston, South Carolina 29425.
Genkyotex, 16 Chemin des Aulx, CH-1228 Plan-les-Ouates Geneva, Switzerland, and.
the Division of Pulmonary, Allergy, and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama 35294-0006.
From the Department of Regenerative Medicine and Cell Biology,


Idiopathic pulmonary fibrosis (IPF) is a progressive clinical syndrome of fatal outcome. The lack of information about the signaling pathways that sustain fibrosis and the myofibroblast phenotype has prevented the development of targeted therapies for IPF. Our previous study showed that isolated fibrogenic lung fibroblasts have high endogenous levels of the hyaluronan receptor, CD44V6 (CD44 variant containing exon 6), which enhances the TGFβ1 autocrine signaling and induces fibroblasts to transdifferentiate into myofibroblasts. NADPH oxidase 4 (NOX4) enzyme, which catalyzes the reduction of O2 to hydrogen peroxide (H2O2), has been implicated in the cardiac and lung myofibroblast phenotype. However, whether CD44V6 regulates NOX4 to mediate tissue repair and fibrogenesis is not well-defined. The present study assessed the mechanism of how TGF-β-1-induced CD44V6 regulates the NOX4/reactive oxygen species (ROS) signaling that mediates the myofibroblast differentiation. Specifically, we found that NOX4/ROS regulates hyaluronan synthesis and the transcription of CD44V6 via an effect upon AP-1 activity. Further, CD44V6 is part of a positive-feedback loop with TGFβ1/TGFβRI signaling that acts to increase NOX4/ROS production, which is required for myofibroblast differentiation, myofibroblast differentiation, myofibroblast extracellular matrix production, myofibroblast invasion, and myofibroblast contractility. Both NOX4 and CD44v6 are up-regulated in the lungs of mice subjected to experimental lung injury and in cases of human IPF. Genetic (CD44v6 shRNA) or a small molecule inhibitor (CD44v6 peptide) targeting of CD44v6 abrogates fibrogenesis in murine models of lung injury. These studies support a function for CD44V6 in lung fibrosis and offer proof of concept for therapeutic targeting of CD44V6 in lung fibrosis disorders.


CD44; NOx; differentiation; hyaluronan; reactive oxygen species (ROS)

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