Tissue inhibitor of metalloproteinases-1 promotes liver fibrosis development in a transgenic mouse model

Hepatology. 2000 Dec;32(6):1248-54. doi: 10.1053/jhep.2000.20521.


Tissue inhibitor of metalloproteinases-1 (TIMP-1) has been shown to be increased in liver fibrosis development both in murine experimental models and human samples. However, the direct role of TIMP-1 during liver fibrosis development has not been defined. To address this issue, we developed transgenic mice overexpressing human TIMP-1 (hTIMP-1) in the liver under control of the albumin promoter/ enhancer. A model of CCl(4)-induced hepatic fibrosis was used to assess the extent of fibrosis development in TIMP-1 transgenic (TIMP-Tg) mice and control hybrid (Cont) mice. Without any treatment, overexpression of TIMP-1 itself did not induce liver fibrosis. There were no significant differences of pro-(alpha1)-collagen-I, (alpha2)-collagen-IV, and alpha-smooth muscle actin (alpha-SMA) mRNA expression in the liver between TIMP-Tg and Cont-mice, suggesting that overexpression of TIMP-1 itself did not cause hepatic stellate cell (HSC) activation. After 4-week treatment with CCl(4), however, densitometric analysis revealed that TIMP-Tg-mice had a seven-fold increase in liver fibrosis compared with the Cont-mice. The hepatic hydroxyproline content and serum hyaluronic acid were also significantly increased in TIMP-Tg-mice, whereas CCl(4)-induced liver dysfunction was not altered. An active form of matrix metalloproteinases-2 (MMP-2) level in the liver of TIMP-Tg-mice was decreased relative to that in Cont-mice because of the transgenic TIMP-1. Immunohistochemical analysis revealed that collagen-I and collagen-IV accumulation was markedly increased in the liver of CCl(4)-treated TIMP-Tg-mice with a pattern similar to that of alpha-SMA positive cells. These results suggest that TIMP-1 does not by itself result in liver fibrosis, but strongly promotes liver fibrosis development.

MeSH terms

  • Actins / genetics
  • Actins / metabolism
  • Animals
  • Carbon Tetrachloride / pharmacology
  • Collagen / genetics
  • Humans
  • Immunohistochemistry
  • Liver / drug effects
  • Liver / enzymology
  • Liver / metabolism
  • Liver Cirrhosis / chemically induced*
  • Matrix Metalloproteinase 2 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Mice, Transgenic / genetics
  • Muscle, Smooth / metabolism
  • RNA, Messenger / metabolism
  • Reference Values
  • Tissue Inhibitor of Metalloproteinase-1* / genetics


  • Actins
  • RNA, Messenger
  • Tissue Inhibitor of Metalloproteinase-1
  • Collagen
  • Carbon Tetrachloride
  • Matrix Metalloproteinase 2