Tissue inhibitor of metalloproteinase-1: Strong promotion of liver fibrosis development in the transgenic mouse model

The tissue inhibitor of metalloproteinases-1 (TIMP-1) reportedly increases during liver fibrosis development, but the direct role of TIMP-1 has not been defined. To elucidate the role of TIMP-1 in liver fibrogenesis, we developed liver-targeted TIMP-1 transgenic mice under the control of albumin promoter/enhancer. A model of CCl4-induced hepatic fibrosis was used to assess the extent of fibrosis development in TIMP-1 transgenic (TIMP-Tg) mice and control hybrid mice. With no treatment, overexpression of TIMP-1 in the liver did not induce liver fibrosis. After 4 weeks of treatment with CCl4, however, a densitometric analysis revealed that the TIMP-Tg mice had a sevenfold increase in Liver fibrosis compared to the control mice. The hepatic collagen and hydroxyproline content and serum fibrosis markers, such as 7S collagen and P-III-N-P, were also significantly increased in the TIMP-Tg mice. Furthermore, immunohistochemical analysis showed that collagen I and collagen IV accumulation was markedly increased along the sinusoidal lining in the liver of the TIMP-Tg mice with a pattern similar to that of smooth muscle alpha -actin (alpha -SMA)positive cells. Activated hepatic stellate cells (HSCs) from TIMP-Tg mice displayed markedly increased RNA expression of procollagen I and collagen IV in response to exogenous recombinant TIMP-1. These results suggest that TIMP-1 does not by itself result in liver fibrogenesis but strongly promotes liver fibrosis development in the transgenic mice through HSC stimulation.