MMPs and TIMPs expression in hepatic stellate cells

Hepatic stellate cells (HSCs) are the main cell type to produce ECM as well as matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) in the liver, and play important roles in regulating the circumstances of ECM in the liver. We focused on MMPs and TIMPs expression in stellate cells. In normal HSCs, MMP-1, -2, -3, -9, -10, -13, -14, -15, and -16 and TIMP-1, -2 and -3 were detected. In activated HSCs during culture in vitro, expression of MMP-1, -3, -9, and -13 were decreased, but MMP-2 and -14 and TIMP-1 and -2 were increased. HSCs in fibrotic liver also show the same regulation as in vitro. Nuclear factors SP-1, BTEB 1, and KLF 6 are related to the early activation of HSCs. ECM also regulates the expression of MMPs. When HSCs were cultured in three-dimensional type I collagen gel, expression of MMP-3, -9, -13, and -14 were markedly enhanced, although MMP-2 did not change. Signalling pathway of MMP-9 expression was examined, and was clarified that ERK-1, -2 pathway through integrin α₂β₁ was important for the induction of MMP-9.