Schaefer Benjamin, Rivas-Estilla Ana María, Meraz-Cruz Noemí, Reyes-Romero Miguel Arturo, Hernández-Nazara Zamira H, Domínguez-Rosales José-Alfredo, Schuppan Detlef, Greenwel Patricia, Rojkind Marcos
Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York, USA.
Am J Pathol. 2003 Jun;162(6):1771-80. doi: 10.1016/S0002-9440(10)64312-X.
Collagen degradation by matrix metalloproteinases is the limiting step in reversing liver fibrosis. Although collagen production in cirrhotic livers is increased, the expression and/or activity of matrix metalloproteinases could be normal, increased in early fibrosis, or decreased during advanced liver cirrhosis. Hepatic stellate cells are the main producers of collagens and matrix metalloproteinases in the liver. Therefore, we sought to investigate whether they simultaneously produce alpha1(I) collagen and matrix metalloproteinase-13 mRNAs. In this communication we show that expression of matrix metalloproteinase-13 mRNA is reciprocally modulated by tumor necrosis factor-alpha and transforming growth factor-beta1. When hepatic stellate cells are co-cultured with hepatocytes, matrix metalloproteinase-13 mRNA is up-regulated and alpha1(I) collagen is down-regulated. Injuring hepatocytes with galactosamine further increased matrix metalloproteinase-13 mRNA production. Confocal microscopy and differential centrifugation of co-cultured cells revealed that matrix metalloproteinase-13 is localized mainly within hepatic stellate cells. Studies performed with various hepatic stellate cell lines revealed that they are heterogeneous regarding expression of matrix metalloproteinase-13. Those with myofibroblastic phenotypes produce more type I collagen whereas those resembling freshly isolated hepatic stellate cells express matrix metalloproteinase-13. Overall, these findings strongly support the notion that alpha1(I) collagen and matrix metalloproteinase-13 mRNAs are reciprocally modulated.
基质金属蛋白酶介导的胶原蛋白降解是逆转肝纤维化的限速步骤。尽管肝硬化肝脏中胶原蛋白的生成增加，但基质金属蛋白酶的表达和/或活性可能正常、在早期纤维化时增加或在晚期肝硬化时降低。肝星状细胞是肝脏中胶原蛋白和基质金属蛋白酶的主要产生者。因此，我们试图研究它们是否同时产生α1(I)胶原蛋白和基质金属蛋白酶-13的信使核糖核酸。在本报告中，我们表明基质金属蛋白酶-13信使核糖核酸的表达受肿瘤坏死因子-α和转化生长因子-β1的反向调节。当肝星状细胞与肝细胞共培养时，基质金属蛋白酶-13信使核糖核酸上调而α1(I)胶原蛋白下调。用半乳糖胺损伤肝细胞可进一步增加基质金属蛋白酶-13信使核糖核酸的产生。共培养细胞的共聚焦显微镜检查和差速离心显示，基质金属蛋白酶-13主要定位于肝星状细胞内。对各种肝星状细胞系进行的研究表明，它们在基质金属蛋白酶-13的表达方面具有异质性。具有肌成纤维细胞表型的细胞产生更多的I型胶原蛋白，而那些类似于新鲜分离的肝星状细胞的细胞则表达基质金属蛋白酶-13。总体而言，这些发现有力地支持了α1(I)胶原蛋白和基质金属蛋白酶-13信使核糖核酸受反向调节这一观点。
