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(American Journal of Pathology. 2003;162:1771-1780.)
© 2003 American Society for Investigative Pathology

Reciprocal Modulation of Matrix Metalloproteinase-13 and Type I Collagen Genes in Rat Hepatic Stellate Cells

Benjamin Schaefer*, Ana María Rivas-Estilla*, Noemí Meraz-Cruz*, Miguel Arturo Reyes-Romero*, Zamira H. Hernández-Nazara*{dagger}, José-Alfredo Domínguez-Rosales*{dagger}, Detlef Schuppan{ddagger}, Patricia Greenwel§ and Marcos Rojkind*{dagger}

From the Marion Bessin Liver Research Center* and the Departments of Medicine and Pathology, Albert Einstein College of Medicine, Bronx, New York; the Department of Medicine I,{ddagger} Klinikum B. Franklin, Free University of Berlin, Berlin, Germany; the Department of Biochemistry and Molecular Biology,§ Brookdale Center, Mount Sinai School of Medicine, New York, New York; and the Department of Clinical Investigation,{dagger} Experimental Pathology Section, Walter Reed Army Medical Center, Washington, D.C.

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 {alpha}1(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-ß1. When hepatic stellate cells are co-cultured with hepatocytes, matrix metalloproteinase-13 mRNA is up-regulated and {alpha}1(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 {alpha}1(I) collagen and matrix metalloproteinase-13 mRNAs are reciprocally modulated.




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