Journal Article

Tartrate-resistant acid phosphatase 5 promotes pulmonary fibrosis by modulating β-catenin signaling

Wang, Yi, Zhou, Qing, Liu, Juan, Hu, Yinan, Wang, Qi, Xiong, Weining, Deng, Yanhan, Zhang, Lei, Yu, Jun, Xu, Yongjian

2022

Overview

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease with limited therapeutic options. Tartrate-resistant acid phosphatase 5 (ACP5) performs a variety of functions. However, its role in IPF remains unclear. Here, we demonstrate that the levels of ACP5 are increased in IPF patient samples and mice with bleomycin (BLM)-induced pulmonary fibrosis. In particular, higher levels of ACP5 are present in the sera of IPF patients with a diffusing capacity of the lungs for carbonmonoxide (DLCO) less than 40% of the predicted value. Additionally, Acp5 deficiency protects mice from BLM-induced lung injury and fibrosis coupled with a significant reduction of fibroblast differentiation and proliferation. Mechanistic studies reveal that Acp5 is upregulated by transforming growth factor-β1 (TGF-β1) in a TGF-β receptor 1 (TGFβR1)/Smad family member 3 (Smad3)-dependent manner, after which Acp5 dephosphorylates p-β-catenin at serine 33 and threonine 41, inhibiting the degradation of β-catenin and subsequently enhancing β-catenin signaling in the nucleus, which promotes the differentiation, proliferation and migration of fibroblast. More importantly, the treatment of mice with Acp5 siRNA-loaded liposomes or Acp5 inhibitor reverses established lung fibrosis. In conclusions, Acp5 is involved in the initiation and progression of pulmonary fibrosis and strategies aimed at silencing or suppressing Acp5 could be considered as potential therapeutic approaches against pulmonary fibrosis. Idiopathic pulmonary fibrosis is a fatal lung disease with limited treatment options. Here the authors show that tartrate-resistant acid phosphatase 5 (Acp5) promotes lung fibrosis by enhancing beta-catenin signaling and that inhibition of Acp5 can reverse stablished pulmonary fibrosis.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/51 / 38/35 / 42 / 42/89 / 631/80/304 / 631/80/86 / 692/699/1785 / 96/1 / 96/95 / Acid phosphatase / Acid phosphatase (tartrate-resistant) / Acid resistance / Animals / beta Catenin - genetics / beta Catenin - metabolism / Bleomycin / Bleomycin - administration & dosage / Carbon Monoxide - metabolism / Cell Differentiation / Cell Movement / Cell Proliferation / Differentiation / Disease Models, Animal / Fibroblasts / Fibroblasts - metabolism / Fibroblasts - pathology / Fibrosis / Gene Expression Regulation / Growth factors / Humanities and Social Sciences / Humans / Injury prevention / Lung - metabolism / Lung - pathology / Lung diseases / Male / Mice / multidisciplinary / Patients / Phosphatase / Phosphorylation / Pulmonary fibrosis / Pulmonary Fibrosis - genetics / Pulmonary Fibrosis - metabolism / Pulmonary Fibrosis - pathology / Pulmonary Fibrosis - prevention & control / Respiratory Function Tests / RNA, Small Interfering - genetics / RNA, Small Interfering - metabolism / Science / Science (multidisciplinary) / Signal Transduction / Signaling / siRNA / Smad protein / Smad3 protein / Smad3 Protein - genetics / Smad3 Protein - metabolism / Tartrate-Resistant Acid Phosphatase - antagonists & inhibitors / Tartrate-Resistant Acid Phosphatase - genetics / Tartrate-Resistant Acid Phosphatase - metabolism / Threonine / Transforming Growth Factor beta1 - genetics / Transforming Growth Factor beta1 - metabolism / Transforming growth factor-b1 / β-Catenin