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: Yael Aschner, Anthony P Khalifah, Natalie Briones, Cory Yamashita, Lior Dolgonos, Scott K Young, Megan N Campbell, David W H Riches, Elizabeth F Redente, William J Janssen, Peter M Henson, Jan Sap, Nathalie Vacaresse, Andras Kapus, Christopher A G McCulloch, Rachel L Zemans, Gregory P Downey
• Journal: The American journal of pathology (Am J Pathol) Vol. 184 Issue 5 Pg. 1489-502 (May 2014) ISSN: 1525-2191 [Electronic] United States
• PMID: 24650563 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Chemical References

• Cytokines
• Receptors, Transforming Growth Factor beta
• Smad Proteins
• Transforming Growth Factor beta
• Bleomycin
• Receptor-Like Protein Tyrosine Phosphatases, Class 4

Topics

• Adenoviridae
• Animals
• Bleomycin
• Cytokines (biosynthesis)
• Fibroblasts (pathology)
• Gene Deletion
• Genes, Reporter
• Lung (pathology)
• Mice
• Mice, Inbred C57BL
• NIH 3T3 Cells
• Pneumonia (complications, pathology)
• Pulmonary Fibrosis (complications, pathology, prevention & control)
• Receptor-Like Protein Tyrosine Phosphatases, Class 4 (deficiency, metabolism)
• Receptors, Transforming Growth Factor beta (metabolism)
• Signal Transduction
• Smad Proteins (metabolism)
• Transcription, Genetic
• Transforming Growth Factor beta (metabolism)