Matrix degradation in liver fibrosis

Matrix metalloproteinases and their inhibitor, TIMPs play important roles in regulating matrix degradation in liver. In early stage of acute liver injury or regenerating liver after partial hepatectomy, there are increased expressions of MMP-13 and MMP-2 together with sequential increased expressions of TIMP-1 and TIMP-2. In liver fibrosis, there is net inhibition of degradation through the increase of TIMP-1 and TIMP-2 relative to MMP-13 and MMP-2. Hepatic stellate cells produce MMP-2, TIMP-1 and TIMP-2. We focused on the activation mechanism of MMP-2 in liver fibrosis and cultured stellate cells. MT-MMPs, which are known to activate MMP-2, are expressed in liver, and MT-1- and MT-3- MMPs are expressed in stellate cells. Con A, but not cytokines, stimulate MMP-2 activation in stellate cells, partially through the increased expression of MT-1-MMP. These studies suggested that hepatic stellate cells are involved in regulating matrix degradation in liver fibrosis.