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
Abstract
BACKGROUND

Liver fibrosis is a refractory disease whose persistence can eventually induce cirrhosis or even liver cancer. Early liver fibrosis is reversible by intervention. As a member of the transforming growth factor-beta (TGF-β) superfamily, bone morphogenetic protein 7 (BMP7) has anti-liver fibrosis functions. However, little is known about BMP7 expression changes and its potential regulatory mechanism as well as the relationship between BMP7 and TGF-β during liver fibrosis. In addition, the mechanism underlying the anti-liver fibrosis function of BMP7 needs to be further explored.

AIM

To investigate changes in the dynamic expression of BMP7 during liver fibrosis, interactions between BMP7 and TGF-β1, and possible mechanisms underlying the anti-liver fibrosis function of BMP7.

METHODS

Changes in BMP7 expression during liver fibrosis and the interaction between BMP7 and TGF-β1 in mice were observed. Exogenous BMP7 was used to treat mouse primary hepatic stellate cells (HSCs) to observe its 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 received exogenous BMP7 intervention to observe improvement of liver fibrosis by using Masson’s trichrome staining and detecting the expression of the HSC activation indicator alpha-smooth muscle actin (α-SMA) and the collagen formation associated protein type I collagen (Col I). Changes in the dynamic expression of BMP7 during liver fibrosis in the human body were further observed.

RESULTS

In the process of liver fibrosis induced by carbon tetrachloride (CCl4) in mice, BMP7 protein expression first increased, followed by a decrease; there was a similar trend in the human body. This process was accompanied by a sustained increase in TGF-β1 protein expression. In vitro experiment results showed that TGF-β1 inhibited BMP7 expression in a time- and dose-dependent manner. In contrast, high doses of exogenous BMP7 inhibited TGF-β1-induced activation, migration, and proliferation of HSCs; this inhibitory effect was associated with upregulation of pSmad1/5/8 and downregulation of phosphorylation of Smad3 and p38 by BMP7. In vivo experiment results showed that exogenous BMP7 improved liver fibrosis in mice.

CONCLUSION

During liver fibrosis, BMP7 protein expression first increases and then decreases. This changing trend is associated with inhibition of BMP7 expression by sustained upregulation of TGF-β1 in a time- and dose-dependent manner. Exogenous BMP7 could selectively regulate TGF-β/Smad pathway-associated factors to inhibit activation, migration, and proliferation of HSCs and exert anti-liver fibrosis functions. Exogenous BMP7 has the potential to be used as an anti-liver fibrosis drug.

Keywords: Liver fibrosis; Bone morphogenetic protein; Transforming growth factor; Hepatic stellate cells

Core tip: Liver fibrosis is the repair response of the liver to chronic injury. Its long-term persistence can eventually progress into cirrhosis or even liver cancer. Many cytokines and signaling pathways participate in the development and progression of liver fibrosis. The transforming growth factor-beta (TGF-β) superfamily member bone morphogenetic protein 7 (BMP7) is reported to have anti-fibrosis functions. This study observed changes in the dynamic expression of BMP7 during liver fibrosis, explored the relationship between BMP7 and TGF-β1, and further investigated the possible mechanism underlying the anti-liver fibrosis function of exogenous BMP7 using in vivo and in vitro experiments. This study demonstrated the prospect of exogenous BMP7 application as a potential anti-liver fibrosis drug.