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 protein 4 mediates bile duct ligation induced liver fibrosis through activation of Smad1 and ERK1/2 in rat hepatic stellate cells
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DOI：
10.1002/jcp.20593
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发表时间：
2006-05-01
影响因子：
5.6
通讯作者：
Gong, YW
中科院分区：
文献类型：
--
作者：
Fan, JG;Shen, H;Gong, YW
骨形态发生蛋白是参与细胞分化尤其是骨形态发生的重要细胞因子。肝星状细胞（hepatic stellate cells，HSC）在肝损伤后活化过程中发生转分化。尽管已经证明BMP 2和BMP 4显著增加了培养的HSC中平滑肌α肌动蛋白（α-SMA）的丰度，但是在HSC的活化过程中尚未检查BMP的表达。在本研究中，我们记录了BMP 4在胆管结扎（BDL）大鼠和培养的HSC中的表达。我们发现BDL大鼠肝脏中BMP 4的表达显著升高。BDL后6周，BMP 4蛋白表达出现两个高峰。BDL后Smad 1、ERK 1/2和p38的表达和磷酸化水平也升高。此外，在体外培养24天的HSCs中，BMP 4 mRNA丰度逐渐升高。此外，BMP 4刺激HSC中Smad 1和ERK 1/2的磷酸化。总之，BDL大鼠肝脏和培养的HSC中BMP 4表达显著增加。这些结果表明，BMP 4可能通过激活Smad 1和ERK 1/2介导HSC活化。
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 (alpha-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.