Protein Tyrosine Phosphatase-α Amplifies TGF-β-Dependent Pro-Fibrotic Signaling in Lung Fibroblasts.

Idiopathic pulmonary fibrosis (IPF) is a progressive, often fatal, fibrosing lung disease for which treatment remains suboptimal. Fibrogenic cytokines, including transforming growth factor-beta (TGF-beta), are central to its pathogenesis. Protein tyrosine phosphatase-alpha (PTP alpha) has emerged as a key regulator of fibrogenic signaling in fibroblasts. We have reported that mice globally deficient in PTP alpha (Ptpra(-/-)) were protected from experimental pulmonary fibrosis, in part via alterations in TGF-beta signaling. The goal of this study was to determine the lung cell types and mechanisms by which PTP alpha controls fibrogenic pathways and whether these pathways are relevant to human disease. Immunohistochemical analysis of lungs from patients with IPF revealed that PTP alpha was highly expressed by mesenchymal cells in fibroblastic foci and by airway and alveolar epithelial cells. To determine whether PTP alpha promotes profibrotic signaling pathways in lung fibroblasts and/or epithelial cells, we generated mice with conditional (floxed) Ptpra alleles (Ptpra(-/-)). These mice were crossed with Dermol-Cre or with Sftpc-CreER(T2) mice to delete Ptpra in mesenchymal cells and alveolar type II cells, respectively. Denno1-Cre/Ptpraf/f mice were protected from bleomycin-induced pulmonary fibrosis, whereas Sftpc-CreER(T2)/Ptpra(f/f) mice developed pulmonary fibrosis equivalent to controls. Both canonical and noncanonical TGF-beta signaling and downstream TGF-beta-induced fibrogenic responses were attenuated in isolated Ptpra(-/)(-) compared with wild-type fibroblasts. Furthermore. TGF-beta-induced tyrosine phosphorylation of TGF-alpha type II receptor and of PTP alpha were attenuated in Ptpra(-/-) compared with wild-type fibroblasts. The phenotype of cells genetically deficient in PTP alpha was recapitulated with the use of a Src inhibitor. These findings suggest that PTP alpha amplifies profibrotic TGF-beta-dependent pathway signaling in lung fibroblasts.