Bone morphogenetic protein 4 inhibits pulmonary fibrosis by modulating cellular senescence and mitophagy in lung fibroblasts. Ruijuan Guan, Liang Yuan, Jingpei Li, Jian Wang, Ziying Li, Zhou Cai, Hua Guo, Yaowei Fang, Ran Lin, Wei Liu, Lan Wang, Qiuyu Zheng,Jingyi Xu, You Zhou, Jing Qian, Mingjing Ding, Jieping Luo, Yuanyuan Li, Kai Yang, Dejun Sun, Hongwei Yao, Jianxing He, Wenju Lu
European Respiratory Journal 2022; DOI: 10.1183/13993003.02307-2021
Abstract
Accumulation of myofibroblasts is critical to fibrogenesis in idiopathic pulmonary fibrosis (IPF). Senescence and insufficient mitophagy in fibroblasts contribute to their differentiation into myofibroblasts, thereby promoting the development of lung fibrosis. Bone morphogenetic protein 4 (BMP4), a multifunctional growth factor, is essential for the early stage of lung development, however, the role of BMP4 in modulating lung fibrosis remains unknown.
This study was to evaluate the role of BMP4 in lung fibrosis using BMP4-haplodeleted mice, BMP4-overexpressed mice, primary lung fibroblasts, and lung samples from patients with IPF.
BMP4 expression was down-regulated in IPF lungs and fibroblasts compared to control individuals, negatively correlated with fibrotic genes, and BMP4 decreased with TGF-β1 stimulation in lung fibroblasts in a time- and dose-dependent manner. In mice challenged with bleomycin, BMP4 haploinsufficiency perpetuated activation of lung myofibroblasts and caused accelerated lung function decline, severe fibrosis and mortality. While BMP4 overexpression using AAV9 vectors showed preventative and therapeutic efficacy against lung fibrosis. In vitro, BMP4 attenuated TGF-β1-induced fibroblast-to-myofibroblast differentiation and extracellular matrix (ECM) production by reducing impaired mitophagy and cellular senescence in lung fibroblasts. Whereas Pink1 silencing by shRNA transfection abolished the ability of BMP4 to reverse the TGF-β1-induced myofibroblast differentiation and ECM production, indicating dependence on Pink1-mediated mitophagy. Moreover, the inhibitory effect of BMP4 on fibroblast activation and differentiation was accompanied with an activation of Smad1/5/9 signaling and suppression of TGF-β1-meidtaed Smad2/3 signaling in vivo and in vitro.
In conclusion, strategies for enhancing BMP4 signaling may represent an effective treatment for pulmonary fibrosis.
Footnotes
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- Received August 22, 2021.
- Accepted June 22, 2022.
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