Regulation and significance of hepatocyte-derived matrix metalloproteinases in liver remodeling.

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, TNFalpha, 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 TNFalpha 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 TNFalpha 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. Copyright 2000 Academic Press.