Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.
Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chiayi Chang Gung Memorial Hospital, Puzi City, Taiwan.
Lab Invest. 2018 Aug;98(8):999-1013. doi: 10.1038/s41374-018-0069-9. Epub 2018 May 22.
Transforming growth factor-β (TGF-β) plays a central role in hepatic fibrogenesis. This study investigated the function and mechanism of bone morphogenetic protein-2 (BMP-2) in regulation of hepatic fibrogenesis. BMP-2 expression in fibrotic liver was measured in human tissue microarray and mouse models of liver fibrosis induced by bile duct ligation surgery or carbon tetrachloride administration. Adenovirus-mediated BMP-2 gene delivery was used to test the prophylactic effect on liver fibrosis. Primary hepatic stellate cells (HSC), HSC-T6 and clone-9 cell lines were used to study the interplay between BMP-2 and TGF-β1. Hepatic BMP-2 was localized in parenchymal hepatocytes and activated HSCs and significantly decreased in human and mouse fibrotic livers, showing an opposite pattern of hepatic TGF-β1 contents. BMP-2 gene delivery alleviated the elevations of serum hepatic enzymes, cholangiocyte marker CK19, HSC activation markers, and liver fibrosis in both models. Mechanistically, exogenous TGF-β1 dose dependently reduced BMP-2 expression, whereas BMP-2 significantly suppressed expression of TGF-β and its cognate type I and II receptor peptides, as well as the induced Smad3 phosphorylation levels in primary mouse HSCs. Aside from its suppressive effects on cell proliferation and migration, BMP-2 treatment prominently attenuated the TGF-β1-stimulated α-SMA and fibronectin expression, and reversed the TGF-β1-modulated epithelial-to-mesenchymal transition marker expression in mouse HSCs. The mutual regulation between BMP-2 and TGF-β1 signaling axes may constitute the anti-fibrogenic mechanism of BMP-2 in the pathogenesis of liver fibrosis. BMP-2 may potentially serve as a novel therapeutic target for treatment of liver fibrosis.
转化生长因子-β（TGF-β）在肝纤维化中起着核心作用。本研究探讨了骨形态发生蛋白-2（BMP-2）在调节肝纤维化中的作用和机制。通过人组织微阵列和胆管结扎术或四氯化碳给药诱导的小鼠肝纤维化模型，测量了纤维化肝脏中的 BMP-2 表达。腺病毒介导的 BMP-2 基因传递用于测试对肝纤维化的预防作用。原代肝星状细胞（HSC）、HSC-T6 和 clone-9 细胞系用于研究 BMP-2 和 TGF-β1 之间的相互作用。肝 BMP-2 定位于实质肝细胞和活化的 HSC 中，在人和小鼠纤维化肝脏中显著降低，显示出与肝 TGF-β1 含量相反的模式。BMP-2 基因传递减轻了两种模型中血清肝酶、胆管细胞标志物 CK19、HSC 活化标志物和肝纤维化的升高。从机制上讲，外源性 TGF-β1 呈剂量依赖性降低 BMP-2 表达，而 BMP-2 显著抑制 TGF-β 及其同源 I 型和 II 型受体肽的表达，以及诱导的 Smad3 磷酸化水平在原代小鼠 HSC 中。除了对细胞增殖和迁移的抑制作用外，BMP-2 处理还明显减弱了 TGF-β1 刺激的α-SMA 和纤维连接蛋白表达，并逆转了 TGF-β1 调节的上皮-间充质转化标志物表达在小鼠 HSCs 中。BMP-2 和 TGF-β1 信号轴之间的相互调节可能构成 BMP-2 在肝纤维化发病机制中的抗纤维化机制。BMP-2 可能作为治疗肝纤维化的一种新的治疗靶点。
