Basic Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Aug 14, 2019; 25(30): 4222-4234
Published online Aug 14, 2019. doi: 10.3748/wjg.v25.i30.4222
Bone morphogenetic protein-7 represses hepatic stellate cell activation and liver fibrosis via regulation of TGF-β/Smad signaling pathway
Gao-Liang Zou, Shi Zuo, Shuang Lu, Rui-Han Hu, Yin-Ying Lu, Jing Yang, Kai-Sheng Deng, Ye-Ting Wu, Mao Mu, Juan-Juan Zhu, Jing-Zhang Zeng, Bao-Fang Zhang, Xian Wu, Xue-Ke Zhao, Hai-Yang Li
Gao-Liang Zou, Shuang Lu, Rui-Han Hu, Jing Yang, Kai-Sheng Deng, Ye-Ting Wu, Mao Mu, Juan-Juan Zhu, Jing-Zhang Zeng, Bao-Fang Zhang, Xian Wu, Xue-Ke Zhao, Department of Infectious Diseases, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China
Shi Zuo, Hai-Yang Li, Department of Hepatobiliary Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China
Yin-Ying Lu, Comprehensive Liver Cancer Center, 302 Hospital, Beijing 100039, China
Author contributions: Zhao XK and Li HY designed the study; Zou GL, Zuo S, and Lu S carried out most of the experiments and wrote the article; all authors contributed to the design and interpretation of the study; Zou GL, Zuo S, and Lu S contributed equally to this work.
Supported by the National Natural Science Foundation of China, No. 81560104 and No. 81860115.
Institutional animal care and use committee statement: This study was approved by the Institutional Animal Care and Use Committee of the Affiliated Hospital of Guizhou Medical University.
Institutional review board statement: This study was approved by the Institutional Review Board of the Affiliated Hospital of Guizhou Medical University.
Conflict-of-interest statement: The authors declare that there is no conflict of interest related to this study.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines and prepared the manuscript accordingly.
Open-Access: This is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Corresponding author: Xue-Ke Zhao, MD, PhD, Adjunct Professor, Department of Infectious Diseases, Affiliated Hospital of Guizhou Medical University, No. 28, Guiyi Road, Guiyang 550004, Guizhou Province, China. zhaoxueke1@163.com
Telephone: +86-851-86773914 Fax: +86-851-86741623
Received: April 16, 2019
Peer-review started: April 16, 2019
First decision: June 10, 2019
Revised: June 25, 2019
Accepted: July 5, 2019
Article in press: July 5, 2019
Published online: August 14, 2019
Processing time: 120 Days and 21.9 Hours
ARTICLE HIGHLIGHTS
Research background

Liver fibrosis is a refractory disease. With disease progression, it can eventually progress into liver cirrhosis or even liver cancer, which severely threatens human health and brings heavy economic burdens. It has been confirmed that early liver fibrosis is reversible after intervention and that bone morphogenetic protein 7 (BMP7) has anti-fibrosis functions. However, the relationship between BMP7 expression and liver fibrosis and the specific mechanism underlying the anti-liver fibrosis function are still not very clear. It is necessary to perform further studies and provide theoretical support for application of exogenous BMP7 in anti-liver fibrosis.

Research motivation

The imbalance of the BMP7/transforming growth factor-beta (TGF-β1) ratio plays a very important role in the development and progression of organ fibrosis. It has been reported that BMP7 has an anti-liver fibrosis function. However, the mutual regulatory relationship between BMP7 and TGF-β1 and the mechanism underlying the anti-fibrosis function of BMP7 still require further elucidation. Therefore, observation of the dynamic changes in BMP7 and TGF-β1 during liver fibrosis and investigation of the possible mechanism underlying the anti-liver fibrosis function of BMP7 have positive significance in the further understanding and treatment of liver fibrosis.

Research objectives

Changes in BMP7 and TGF-β1 expression in the liver fibrosis process were observed to explore the interaction between these two and further study the possible mechanism underlying the anti-liver fibrosis function of BMP7.

Research methods

Dynamic changes in BMP7 in the liver fibrosis process in mice and the interactive relationship between BMP7 and TGF-β1 were observed. Mouse primary HSCs were treated with exogenous BMP7 to observe the effect on activation, migration, and proliferation of HSCs and explore the possible mechanism underlying the anti-liver fibrosis function of BMP7. Mice with liver fibrosis were treated with exogenous BMP7 to observe the improvement of liver fibrosis by using Masson’s trichrome staining and detecting the expression of the HSC activation indicator α-SMA and the collagen formation associated protein Col I. Changes in the dynamic expression of BMP7 in liver fibrosis in the human body were further observed.

Research results

During liver fibrosis in mice, BMP7 expression first increased, followed by a decrease; the same trend was observed in the human body. This change was accompanied by sustained upregulation of TGF-β1 expression. In vitro experiment results showed that TGF-β1 could inhibit BMP7 expression in a time- and dose-dependent manner. In contrast, high doses of exogenous BMP7 could inhibit TGF-β1-induced activation, migration, and proliferation of HSCs; in addition, this inhibitory effect was associated with upregulation of pSmad1/5/8 and downregulation of pSmad3 and p-P38 protein expression by BMP7. In vivo experiment results showed that exogenous BMP7 improved liver fibrosis in mice.

Research conclusions

Our study indicated that BMP7 expression first increased, followed by a decrease, during the liver fibrosis process. This changing trend was associated with inhibition of BMP7 expression by sustained upregulation of TGF-β1 in a time- and dose-dependent manner. High doses of BMP7 exhibited anti-liver fibrosis functions. This function was achieved through inhibition of TGF-β1-induced activation, migration, and proliferation of HSCs. Exogenous BMP7 played an anti-liver fibrosis role that was associated with activating BMP7-pSmad1/5/8 and antagonizing TGF-β1-pSmad3 and p-P38.

Research perspectives

Our results further emphasized the anti-liver fibrosis function of BMP7 and exhibited the relationship between dynamic changes of BMP7 and TGF-β1 in the liver fibrosis process, which is helpful for deepening our understanding of the mechanism of liver fibrosis and has guiding significance in the selection of anti-liver fibrosis targets. The investigation of the anti-liver fibrosis mechanism of BMP7 suggested the prospect of application of exogenous BMP7 as an anti-liver fibrosis drug.