Published online Aug 14, 2019. doi: 10.3748/wjg.v25.i30.4222
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
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.
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.
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.
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.
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.
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.
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.