Reduced expression of BMP3 contributes to the development of pulmonary fibrosis and predicts the unfavorable prognosis in IIP patients

// Xiaoting Yu 1, * , Pan Gu 1, * , Ziling Huang 1, * , Xia Fang 2 , Ying Jiang 3 , Qun Luo 3 , Xia Li 4 , Xuyou Zhu 1 , Mengna Zhan 5 , Junbang Wang 6 , Lichao Fan 7 , Rongchang Chen 3 , Juehua Yu 6 , Yingying Gu 3 , Aibin Liang 2 and Xianghua Yi 1 1 Department of Pathology, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China 2 Department of Biotherapy, Tongji Hosptial, Tongji University School of Medicine, Shanghai 200065, China 3 The State Key Laboratory of Respiratory Disease, Guangzhou Institute of Respiratory Disease, the First Affiliated Hospital, Guangzhou Medical University, Guangzhou, Guangdong 510120, China 4 Department of Respiratory, Shanghai Pulmonary Hospital, Tongji Universiy School of Medicine, Shanghai 200433, China 5 Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, China 6 Stem Cell Translational Research Center, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China 7 Department of Respiratory, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, China * These authors contributed equally to this work Correspondence to: Xianghua Yi, email: yixhxf@163.com Aibin Liang, email: Lab7182@tongji.edu.cn Yingying Gu, email: gyblgyy@126.com Keywords: bone morphogenetic protein 3/BMP3, transforming growth factor-β/TGF-β, idiopathic pulmonary fibrosis/IPF, idiopathic nonspecific interstitial pneumonia/INSIP Received: June 03, 2017      Accepted: July 25, 2017      Published: August 09, 2017 ABSTRACT Idiopathic pulmonary fibrosis (IPF) and idiopathic nonspecific interstitial pneumonia (INSIP) are two related diseases involving varying degrees of pulmonary fibrosis with no effective cure. Bone morphogenetic protein 3 (BMP3) is a member of the transforming growth factor-β (TGF-β) super-family, which has not been implicated in pulmonary fibrosis previously. In this study, we aimed to investigate the potential role of BMP3 playing in pulmonary fibrosis from clinical diagnosis to molecular signaling regulation. RNA sequencing was performed to explore the potential biomarker of IIP patients. The expression of BMP3 was evaluated in 83 cases of IPF and INSIP by immunohistochemistry. The function of BMP3 was investigated in both fibroblast cells and a bleomycin-induced murine pulmonary fibrosis model. The clinical relevance of BMP3 expression were analyzed in 47 IIP patients, which were included in 83 cases and possess more than five-year follow-up data. Both RNA-sequencing and immunohistochemistry staining revealed that BMP3 was significantly down-regulated in lung tissues of patients with IPF and INSIP. Consistently, lower expression of BMP3 also was found in pulmonary fibrotic tissues of bleomycin-induced mice model. Up-regulation of BMP3 prevented pulmonary fibrosis processing through inhibiting cellular proliferation of fibroblasts as well as TGF-β1 signal transduction. Finally, the relatively higher expression of BMP3 in IPF patients was associated with less/worse mortality. Intravenous injection of recombinant BMP3. Taken together, our results suggested that the low expression level of BMP3 may indicate the unfavorable prognosis of IPF patients, targeting BMP3 may represent a novel potential therapeutic method for pulmonary fibrosis management.