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Bone morphogenetic protein-7 represses hepatic stellate cell activation and liver fibrosis via regulation of TGF-β/Smad signaling pathway.
World J Gastroenterol. 2019 Aug 14; 25(30):4222-4234.WJ

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.

Authors+Show Affiliations

Department of Infectious Diseases, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China.Department of Hepatobiliary Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China.Department of Infectious Diseases, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China.Department of Infectious Diseases, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China.Comprehensive Liver Cancer Center, 302 Hospital, Beijing 100039, China.Department of Infectious Diseases, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China.Department of Infectious Diseases, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China.Department of Infectious Diseases, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China.Department of Infectious Diseases, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China.Department of Infectious Diseases, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China.Department of Infectious Diseases, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China.Department of Infectious Diseases, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China.Department of Infectious Diseases, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China.Department of Infectious Diseases, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China. zhaoxueke1@163.com.Department of Hepatobiliary Surgery, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31435175

Citation

Zou, Gao-Liang, et al. "Bone Morphogenetic Protein-7 Represses Hepatic Stellate Cell Activation and Liver Fibrosis Via Regulation of TGF-β/Smad Signaling Pathway." World Journal of Gastroenterology, vol. 25, no. 30, 2019, pp. 4222-4234.
Zou GL, Zuo S, Lu S, et al. Bone morphogenetic protein-7 represses hepatic stellate cell activation and liver fibrosis via regulation of TGF-β/Smad signaling pathway. World J Gastroenterol. 2019;25(30):4222-4234.
Zou, G. L., Zuo, S., Lu, S., Hu, R. H., Lu, Y. Y., Yang, J., Deng, K. S., Wu, Y. T., Mu, M., Zhu, J. J., Zeng, J. Z., Zhang, B. F., Wu, X., Zhao, X. K., & Li, H. Y. (2019). Bone morphogenetic protein-7 represses hepatic stellate cell activation and liver fibrosis via regulation of TGF-β/Smad signaling pathway. World Journal of Gastroenterology, 25(30), 4222-4234. https://doi.org/10.3748/wjg.v25.i30.4222
Zou GL, et al. Bone Morphogenetic Protein-7 Represses Hepatic Stellate Cell Activation and Liver Fibrosis Via Regulation of TGF-β/Smad Signaling Pathway. World J Gastroenterol. 2019 Aug 14;25(30):4222-4234. PubMed PMID: 31435175.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Bone morphogenetic protein-7 represses hepatic stellate cell activation and liver fibrosis via regulation of TGF-β/Smad signaling pathway. AU - Zou,Gao-Liang, AU - Zuo,Shi, AU - Lu,Shuang, AU - Hu,Rui-Han, AU - Lu,Yin-Ying, AU - Yang,Jing, AU - Deng,Kai-Sheng, AU - Wu,Ye-Ting, AU - Mu,Mao, AU - Zhu,Juan-Juan, AU - Zeng,Jing-Zhang, AU - Zhang,Bao-Fang, AU - Wu,Xian, AU - Zhao,Xue-Ke, AU - Li,Hai-Yang, PY - 2019/04/16/received PY - 2019/06/25/revised PY - 2019/07/05/accepted PY - 2019/8/23/entrez PY - 2019/8/23/pubmed PY - 2020/2/15/medline KW - Bone morphogenetic protein KW - Hepatic stellate cells KW - Liver fibrosis KW - Transforming growth factor SP - 4222 EP - 4234 JF - World journal of gastroenterology JO - World J Gastroenterol VL - 25 IS - 30 N2 - 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. SN - 2219-2840 UR - https://www.unboundmedicine.com/medline/citation/31435175/Bone_morphogenetic_protein_7_represses_hepatic_stellate_cell_activation_and_liver_fibrosis_via_regulation_of_TGF_β/Smad_signaling_pathway_ L2 - https://www.wjgnet.com/1007-9327/full/v25/i30/4222.htm DB - PRIME DP - Unbound Medicine ER -