Tacke Frank, Gäbele Erwin, Bataille Frauke, Schwabe Robert F, Hellerbrand Claus, Klebl Frank, Straub Rainer H, Luedde Tom, Manns Michael P, Trautwein Christian, Brenner David A, Schölmerich Jürgen, Schnabl Bernd
Medical Clinic III, University Hospital Aachen, Aachen, Germany.
Dig Dis Sci. 2007 Dec;52(12):3404-15. doi: 10.1007/s10620-007-9758-8. Epub 2007 Apr 6.
Hepatic stellate cells (HSCs) are the main extracellular matrix (ECM)-producing cells in liver fibrogenesis. The excessive synthesis of ECM proteins deteriorates hepatic architecture and results in liver fibrosis and cirrhosis. This study investigated the role of bone morphogenetic protein 7 (BMP7) as a member of the transforming growth factor (TGF)-beta superfamily in chronic liver disease. Plasma levels of BMP7 were significantly elevated in patients with chronic liver disease compared with healthy controls. Immunohistochemistry of cirrhotic human liver demonstrated upregulated BMP7 protein expression in hepatocytes as compared with normal human liver. Because gene expression for all putative BMP7 receptors was induced during the culture activation process of primary human HSCs, we studied the effects of BMP7 on hTERT immortalized human HSCs in vitro. BMP7, as expressed and secreted after infection with adenoviruses encoding BMP7 (AdBMP7), increased proliferation of HSCs. The mRNA and protein expression of type I collagen and fibronectin was increased in BMP7-stimulated HSCs. Elevated systemic and hepatic levels of BMP7 in patients with chronic liver disease may contribute to progression of liver fibrogenesis in vivo.
肝星状细胞（HSCs）是肝纤维化过程中产生细胞外基质（ECM）的主要细胞。ECM蛋白的过度合成会破坏肝脏结构，导致肝纤维化和肝硬化。本研究调查了作为转化生长因子（TGF）-β超家族成员的骨形态发生蛋白7（BMP7）在慢性肝病中的作用。与健康对照相比，慢性肝病患者的血浆BMP7水平显著升高。与正常人类肝脏相比，肝硬化人类肝脏的免疫组织化学显示肝细胞中BMP7蛋白表达上调。由于在原代人HSCs的培养激活过程中，所有假定的BMP7受体的基因表达均被诱导，因此我们在体外研究了BMP7对hTERT永生化人HSCs的影响。用编码BMP7的腺病毒（AdBMP7）感染后表达和分泌的BMP7增加了HSCs的增殖。在BMP7刺激的HSCs中，I型胶原蛋白和纤连蛋白的mRNA和蛋白表达增加。慢性肝病患者全身和肝脏BMP7水平升高可能有助于体内肝纤维化的进展。
