Bone morphogenetic protein 4 mediates bile duct ligation induced liver fibrosis through activation of Smad1 and ERK1/2 in rat hepatic stellate cells

Bone morphogenetic proteins (BMPs) are the important cytokine involving in cell differentiation especially in bone morphogenesis. Hepatic stellate cells (HSCs) undergo a trans-differentiation during their activation after liver injury. Although it has been demonstrated that BMP2 and BMP4 significantly increased the abundance of smooth muscle alpha actin (α-SMA) in cultured HSCs, the expression of BMPs has not been examined during the activation of HSCs. In current study, we documented the expression of BMP4 in bile duct ligation (BDL) rats and HSCs in culture. We have found that the expression of BMP4 was significantly elevated in the liver of BDL rats. The increase in BMP4 protein showed two peaks during 6 weeks after BDL. The expression and phosphorylation of Smad1, ERK1/2 and p38 were also elevated after BDL. Moreover, there was a gradual elevation of BMP4 mRNA abundance during 24 days' in vitro culture of HSCs. Furthermore, BMP4 stimulated phosphorylation of Smad1 and ERK1/2 in HSCs. In conclusion, BMP4 expression was significantly increased in the liver of BDL rats and HSCs in culture. These findings indicate that BMP4 may mediate HSC activation through activation of Smad1 and ERK1/2. J. Cell. Physiol. 207: 499–505, 2006. © 2006 Wiley-Liss, Inc.