Reciprocal modulation of matrix metalloproteinase-13 and type I collagen genes in rat hepatic stellate cells.
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.
Schaefer
Benjamin
B
Marion Bessin Liver Research Center, Albert Einstein College of Medicine, Bronx, New York, USA.
Rivas-Estilla
Ana María
AM
Meraz-Cruz
Noemí
N
Reyes-Romero
Miguel Arturo
MA
Hernández-Nazara
Zamira H
ZH
Domínguez-Rosales
José-Alfredo
JA
Schuppan
Detlef
D
Greenwel
Patricia
P
Rojkind
Marcos
M
D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002460:Cell Line; D002478:Cells, Cultured; D018920:Coculture Techniques; D024042:Collagen Type I / Q000235:genetics* / Q000378:metabolism; D017364:Collagenases / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D022781:Hepatocytes / Q000166:cytology; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D053509:Matrix Metalloproteinase 13; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D051381:Rats; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D024042:Collagen Type I; D012333:RNA, Messenger; C508961:Tgfb1 protein, mouse; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014409:Tumor Necrosis Factor-alpha; D017364:Collagenases; D053509:Matrix Metalloproteinase 13; C507081:Mmp13 protein, mouse; C507083:Mmp13 protein, rat; D020778:Matrix Metalloproteinase 2