Protein tyrosine phosphatase α mediates profibrotic signaling in lung fibroblasts through TGF-β responsiveness
| Autor: | Elizabeth F. Redente, William J. Janssen, Anthony P. Khalifah, David W. H. Riches, Rachel L. Zemans, Nathalie Vacaresse, Cory Yamashita, Lior Dolgonos, Gregory P. Downey, Andras Kapus, Megan Campbell, Yael Aschner, Natalie Briones, Christopher A. McCulloch, Peter M. Henson, Scott K. Young, Jan Sap |
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| Rok vydání: | 2013 |
| Předmět: |
medicine.medical_specialty
Transcription Genetic Pulmonary Fibrosis Smad Proteins Protein tyrosine phosphatase Biology Bleomycin Pathology and Forensic Medicine Adenoviridae chemistry.chemical_compound Mice Genes Reporter Transforming Growth Factor beta Internal medicine Pulmonary fibrosis medicine Animals Fibroblast Lung Receptor-Like Protein Tyrosine Phosphatases Class 4 Regular Article Transforming growth factor beta Pneumonia Fibroblasts medicine.disease 3. Good health CTGF Mice Inbred C57BL Endocrinology medicine.anatomical_structure chemistry Cancer research biology.protein NIH 3T3 Cells Cytokines Signal transduction Receptors Transforming Growth Factor beta Gene Deletion Transforming growth factor Signal Transduction |
| Zdroj: | The American journal of pathology. 184(5) |
| ISSN: | 1525-2191 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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