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.

Deficiency of α7 Nicotinic Acetylcholine Receptor Attenuates Bleomycin-Induced Lung Fibrosis in Mice

“…PTP1B is implicated in α7 nAChR-activation enhanced TGF-β signaling and profibrotic gene transcription mice were protected from pulmonary fibrosis induced by intratracheal BLM, with minimal alterations in the early inflammatory response or production of TGF-β (17). Whether PTP family members share similar features in regulating the development of fibrosis is worth investigating.…”

“…Besides PTP1B, PTP-α (coded by Ptpra) has been reported to play a role in mediating promotion of profibrotic signaling pathways in fibroblasts through control of cellular responsiveness to TGF-β (17). Similar to Chrna7 null mice, Ptpra -/-in vivo, activation of α7 nAChR might preferentially affect TGF-β1 signaling or fibrogenesis in lung fibroblasts rather than epithelial cells.…”

Transforming Growth Factor-β: Master Regulator of the Respiratory System in Health and Disease

“…Recent studies have shown that phosphorylation of tyrosine residues within the cytoplasmic tail of TbRII is essential for Smad-dependent profibrotic signaling within kidney collecting duct cells, and that a tyrosine phosphatase (TCPTP) that dephosphorylates these residues inhibits profibrotic signaling via integrin-dependent mechanisms (28). We have shown that another tyrosine phosphatase, PTPa, promotes TGF-b Smad-dependent responses in vitro in fibroblasts, as well as in murine models of pulmonary fibrosis (29).…”

“…To our knowledge, targeting the TGF-b pathway in other respiratory diseases such as COPD and in the airway remodeling component of chronic asthma, although intuitive, has not yet been attempted. Alternative strategies may also include the targeting of molecules that cross-talk with key components of the TGF-b signaling pathway, such as the PTPa or TRPV4 channels, which could provide selective targeting of pathological TGF-b effects while avoiding the consequences and untoward effects of global TGF-b antagonism (29,95).…”

MicroRNA-483-3p Inhibits Extracellular Matrix Production by Targeting Smad4 in Human Trabecular Meshwork Cells

“…Idiopathic pulmonary fibrosis is characterized by excessive deposition of collagen, other ECM components, and excessive fibroblast proliferation. 30,31 Aschner et al 32 revealed that receptor-type protein tyrosine phosphatase a (PTP-a) promoted profibrotic signaling pathway in fibroblasts by modulating cellular responsiveness to TGF-b. Several studies have indicated that TGF-b could significantly increase the expression of collagen-1 and fibronectin.…”