Protein Tyrosine Phosphatase α Mediates Profibrotic Signaling in Lung Fibroblasts through TGF-β Responsiveness
Protein Tyrosine Phosphatase α Mediates Profibrotic Signaling in Lung Fibroblasts through TGF-β Responsiveness
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DOI：
10.1016/j.ajpath.2014.01.016
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发表时间：
2014-05-01
影响因子：
6
通讯作者：
Downey, Gregory P.
中科院分区：
文献类型：
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作者：
Aschner, Yael;Khalifah, Anthony P.;Downey, Gregory P.
纤维化肺部疾病是一组多样的进行性且往往致命的疾病，治疗选择有限。尽管这些病症的发病机制仍未完全明确，但受体型蛋白酪氨酸磷酸酶α（由PTPRA编码的PTP -α）已成为成纤维细胞信号传导的关键调节因子。我们先前报道过，PTP -α通过整合素介导的信号传导调节细胞对细胞因子和生长因子的反应，并且PTP -α促进基质金属蛋白酶3（一种与肺纤维化相关的基质降解蛋白酶）的成纤维细胞表达。在此，我们试图更直接地确定PTP -α在肺纤维化中的作用。基因缺失PTP -α的小鼠（Ptpra - / -）可免受气管内博来霉素诱导的肺纤维化，早期炎症反应或转化生长因子 -β的产生仅有微小变化。Ptprcri小鼠也可免受腺病毒介导的活性转化生长因子 -β1表达所诱导的肺纤维化。在相互的骨髓嵌合实验中，保护表型与肺实质细胞相关，而非骨髓来源细胞。由于成纤维细胞是组织纤维化的关键促成因素，我们比较了野生型和Ptpra - / -小鼠胚胎及肺成纤维细胞的促纤维化反应。Ptpra - / -成纤维细胞对转化生长因子 -β表现出低反应性，表现为α -平滑肌肌动蛋白、EDA -纤连蛋白、Ⅰ型胶原蛋白和结缔组织生长因子的表达减少。Ptprcri成纤维细胞表现出转化生长因子 -β诱导的Smad2/3转录活性显著减弱。我们得出结论，PTP -α通过控制细胞对转化生长因子 -β的反应性，促进成纤维细胞中的促纤维化信号通路。
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.