Protein Tyrosine Phosphatase α Mediates Profibrotic Signaling in Lung Fibroblasts through TGF-β Responsiveness

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 a (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. Ptprcri mice were also protected from pulmonary fibrosis induced by adenovirat-mediated expression of active TGF-beta 1. 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 aSMA, EDA-fibronectin, collagen 1A, and CTGF. Ptprcri fibroblasts exhibited markedly attenuated TGF-beta induced Smad2/3 transcriptional activity. We conclude that PTP-alpha promotes profibrotic signaling pathways in fibrolasts through control of cellular responsiveness to TGF-beta.