title: Protein tyrosine phosphatase α mediates profibrotic signaling in lung fibroblasts through TGF-β responsiveness.
abstract: Fibrotic lung diseases represent a diverse group of progressive and often fatal disorders with limited treatment options. Although the pathogenesis of these conditions remains incompletely understood, receptor type protein tyrosine phosphatase α (PTP-α encoded by PTPRA) has emerged as a key regulator of fibroblast signaling. We previously reported that PTP-α regulates cellular responses to cytokines and growth factors through integrin-mediated signaling and that PTP-α promotes fibroblast expression of matrix metalloproteinase 3, a matrix-degrading proteinase linked to pulmonary fibrosis. Here, we sought to determine more directly the role of PTP-α in pulmonary fibrosis. Mice genetically deficient in PTP-α (Ptpra(-/-)) were protected from pulmonary fibrosis induced by intratracheal bleomycin, with minimal alterations in the early inflammatory response or production of TGF-β. Ptpra(-/-) mice were also protected from pulmonary fibrosis induced by adenoviral-mediated expression of active TGF-β1. In reciprocal bone marrow chimera experiments, the protective phenotype tracked with lung parenchymal cells but not bone marrow-derived cells. Because fibroblasts are key contributors to tissue fibrosis, we compared profibrotic responses in wild-type and Ptpra(-/-) mouse embryonic and lung fibroblasts. Ptpra(-/-) fibroblasts exhibited hyporesponsiveness to TGF-β, manifested by diminished expression of αSMA, EDA-fibronectin, collagen 1A, and CTGF. Ptpra(-/-) fibroblasts exhibited markedly attenuated TGF-β-induced Smad2/3 transcriptional activity. We conclude that PTP-α promotes profibrotic signaling pathways in fibroblasts through control of cellular responsiveness to TGF-β.
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, National Jewish Health, Denver, Colorado; Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, Aurora, Colorado.
authors.forename: Yael
authors.initials: Y
authors.lastname: Aschner
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, National Jewish Health, Denver, Colorado; Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, Aurora, Colorado.
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Khalifah
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, National Jewish Health, Denver, Colorado.
authors.forename: Natalie
authors.initials: N
authors.lastname: Briones
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, National Jewish Health, Denver, Colorado; Division of Respirology, Department of Medicine, University of Western Ontario, London, Ontario, Canada.
authors.forename: Cory
authors.initials: C
authors.lastname: Yamashita
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, National Jewish Health, Denver, Colorado; Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, Aurora, Colorado.
authors.forename: Lior
authors.initials: L
authors.lastname: Dolgonos
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, National Jewish Health, Denver, Colorado.
authors.forename: Scott K
authors.initials: SK
authors.lastname: Young
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, National Jewish Health, Denver, Colorado.
authors.forename: Megan N
authors.initials: MN
authors.lastname: Campbell
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, Colorado.
authors.forename: David W H
authors.initials: DW
authors.lastname: Riches
authors.affiliation: Department of Pediatrics, National Jewish Health, Denver, Colorado.
authors.forename: Elizabeth F
authors.initials: EF
authors.lastname: Redente
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, National Jewish Health, Denver, Colorado; Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, Aurora, Colorado.
authors.forename: William J
authors.initials: WJ
authors.lastname: Janssen
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, National Jewish Health, Denver, Colorado; Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, Aurora, Colorado; Department of Pediatrics, National Jewish Health, Denver, Colorado; Department of Immunology, University of Colorado, Aurora, Colorado.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Henson
authors.affiliation: Unit of Epigenetics and Cell Fate, UMR7216, University of Paris-Diderot, Paris, France.
authors.forename: Jan
authors.initials: J
authors.lastname: Sap
authors.affiliation: Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Vacaresse
authors.affiliation: Keenan Research Center, Li Ka Shing Knowledge Institute-St. Michael's Hospital, University of Toronto, Ontario, Canada; Department of Surgery, University of Toronto, Ontario, Canada.
authors.forename: Andras
authors.initials: A
authors.lastname: Kapus
authors.affiliation: Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Christopher A G
authors.initials: CA
authors.lastname: McCulloch
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, National Jewish Health, Denver, Colorado; Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, Aurora, Colorado.
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Zemans
authors.affiliation: Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, National Jewish Health, Denver, Colorado; Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, Aurora, Colorado; Department of Pediatrics, National Jewish Health, Denver, Colorado; Department of Immunology, University of Colorado, Aurora, Colorado. Electronic address: downeyg@njhealth.org.
authors.forename: Gregory P
authors.initials: GP
authors.lastname: Downey
mesh_terms: D000256:Adenoviridae; D000818:Animals; D001761:Bleomycin; D016207:Cytokines / Q000096:biosynthesis; D005347:Fibroblasts / Q000473:pathology*; D017353:Gene Deletion; D017930:Genes, Reporter; D008168:Lung / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D011014:Pneumonia / Q000150:complications / Q000473:pathology; D011658:Pulmonary Fibrosis / Q000150:complications / Q000473:pathology* / Q000517:prevention & control; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4 / Q000172:deficiency / Q000378:metabolism*; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D051785:Smad Proteins / Q000378:metabolism; D014158:Transcription, Genetic; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D016207:Cytokines; D018125:Receptors, Transforming Growth Factor beta; D051785:Smad Proteins; D016212:Transforming Growth Factor beta; D001761:Bleomycin; D054630:Receptor-Like Protein Tyrosine Phosphatases, Class 4