| First Author | Aschner Y | Year | 2014 |
| Journal | Am J Pathol | Volume | 184 |
| Issue | 5 | Pages | 1489-502 |
| PubMed ID | 24650563 | Mgi Jnum | J:208642 |
| Mgi Id | MGI:5563869 | Doi | 10.1016/j.ajpath.2014.01.016 |
| Citation | Aschner Y, et al. (2014) Protein Tyrosine Phosphatase alpha Mediates Profibrotic Signaling in Lung Fibroblasts through TGF-beta Responsiveness. Am J Pathol 184(5):1489-502 |
| abstractText | 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 alpha (PTP-alpha encoded by PTPRA) has emerged as a key regulator of fibroblast signaling. We previously reported that PTP-alpha regulates cellular responses to cytokines and growth factors through integrin-mediated signaling and that PTP-alpha 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-alpha in pulmonary fibrosis. Mice genetically deficient in PTP-alpha (Ptpra(-/-)) were protected from pulmonary fibrosis induced by intratracheal bleomycin, with minimal alterations in the early inflammatory response or production of TGF-beta. Ptpra(-/-) mice were also protected from pulmonary fibrosis induced by adenoviral-mediated expression of active TGF-beta1. 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-beta, manifested by diminished expression of alphaSMA, EDA-fibronectin, collagen 1A, and CTGF. Ptpra(-/-) fibroblasts exhibited markedly attenuated TGF-beta-induced Smad2/3 transcriptional activity. We conclude that PTP-alpha promotes profibrotic signaling pathways in fibroblasts through control of cellular responsiveness to TGF-beta. |
