Regulation and Significance of Hepatocyte-Derived Matrix Metalloproteinases in Liver Remodeling

• Published in: Biochemical and biophysical research communications Vol. 272; no. 3; pp. 681 - 686
• Main Authors: Haruyama, Takahiro, Ajioka, Itsuki, Akaike, Toshihiro, Watanabe, Yoshifumi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16-06-2000
• Subjects: Androstadienes - pharmacology; Animals; Cell Division - drug effects; Cell Movement - drug effects; Cell Size - drug effects; Cells, Cultured; Colchicine - pharmacology; Collagen - metabolism; Cytochalasin D - pharmacology; Drug Synergism; Enzyme Induction - drug effects; Hepatocyte Growth Factor - pharmacology; Humans; Liver - cytology; Liver - drug effects; Liver - enzymology; Liver - physiology; Liver Regeneration - drug effects; Matrix Metalloproteinase 2 - genetics; Matrix Metalloproteinase 2 - metabolism; Matrix Metalloproteinase 9 - biosynthesis; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Matrix Metalloproteinase Inhibitors; Phosphatidylinositol 3-Kinases - antagonists & inhibitors; Phosphatidylinositol 3-Kinases - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; Signal Transduction - drug effects; Tissue Inhibitor of Metalloproteinase-1 - pharmacology; Tumor Necrosis Factor-alpha - pharmacology
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1006/bbrc.2000.2837

Regulation in expression and activation of proteinases is one of the most important mechanisms in organ morphogenesis. In this study, we investigated the expression of MMPs in primary hepatocytes and their roles in liver remodeling. A hepatocyte proliferation initiating cytokine, TNFα, induced MMP-9 expression in these cells while the expression of MMP-2 did not change by zymography analysis. Interestingly, both the induced MMP-9 expression and hepatocyte proliferation by TNFα were synergistically enhanced by HGF in vitro. The increased proliferation was suppressed by MMP inhibitor TIMP-1, suggesting that cytokine-induced MMP regulates proliferation. The increased expression of MMP-9 by the cytokines was inhibited by cytochalasin D or colchicine but not by PI3 kinase inhibitor wortmannin. In addition, co-stimulation by TNFα and HGF of spheroidal hepatocytes cultured in 3-dimensional collagen gel drastically induced morphological changes by cell extension and migration in the gel, which was in parallel with the induced expression of MMP-9 and was inhibited by TIMP-1 and -2. The MMP activity was also detected in vivo in the regenerating liver after partial hepatectomy by in situ zymography. These results suggest the roles of MMPs produced by parenchymal cells in liver remodeling.