Abstract
Liver fibrosis is a common phenomenon that is associated with several pathologies and is characterized by excessive extracellular matrix deposition that leads to progressive liver dysfunction. Bone morphogenetic protein 9 (BMP9) is the most recently discovered member of the BMP family. BMP9 bound with high affinity to activin receptor-like kinase 1 (ALK1) and endoglin in non-parenchymal liver cells. In addition, BMP9 activated Smad1/Smad5/Smad8 and induced the expression of the target genes inhibitor of differentiation 1 (Id1), hepcidin, Snail and the co-receptor endoglin in liver cells. Although the role of BMP9 in liver fibrosis is currently poorly understood, the presence of BMP9-activated proteins and its target genes have been reported to be associated with liver fibrosis development. This review summarizes the indirect connection between BMP9 and liver fibrosis, with a focus on the BMP9 signaling pathway members ALK1, endoglin, Id1, hepcidin and Snail. The observations on the role of BMP9 in regulating liver fibrosis may help in understanding the pathology mechanisms of liver disease. Furthermore, BMP9 could be served as a potent biomarker and the target of potential therapeutic drugs to treat hepatocytes fibrosis.
Highlights
Liver fibrosis is a pathological process in which excessive precipitation of diffusive liver extracellular matrix (ECM) occurs as a result of intrahepatic connective tissue dysplasia caused by a variety of pathogenic factors
A variety of signal transduction pathways and cytokines have been demonstrated to regulate the development of liver fibrosis, including transforming growth factor-β1 (TGF-β1), bone morphogenetic protein 7 (BMP7), and Smad [6,7,8]
Few studies have investigated the direct correlation between Bone morphogenetic protein 9 (BMP9) and liver fibrosis, the available results demonstrate that BMP9 is primarily expressed in liver cells and acted in both autocrine and paracrine manners
Summary
Liver fibrosis is a pathological process in which excessive precipitation of diffusive liver extracellular matrix (ECM) occurs as a result of intrahepatic connective tissue dysplasia caused by a variety of pathogenic factors. A variety of signal transduction pathways and cytokines have been demonstrated to regulate the development of liver fibrosis, including transforming growth factor-β1 (TGF-β1), bone morphogenetic protein 7 (BMP7), and Smad [6,7,8]. Previous experiments demonstrated that HSCs [31], bile duct ECs and Kupffer cells [14,32] primarily express the type I receptor of ALK1, which can bind to BMP9 and subsequently activate intracellular signaling pathways [24]. Ligand-activated ALK1 activates the target gene Id1 through the Smad pathway, thereby inducing HSCs to differentiate into fibroblasts, which produce ECM proteins [39,40]. The over-expression of ALK1 leads to up-regulation of the mesenchymal cell marker vimentin and down-regulation of E-cadherin [29]
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