Tissue inhibitor of metalloproteinases-1 attenuates spontaneous liver fibrosis resolution in the transgenic mouse

Hepatology. 2002 Oct;36(4 Pt 1):850-60. doi: 10.1053/jhep.2002.35625.


It has been suggested that the tissue inhibitor of metalloproteinases-1 (TIMP-1) is involved in spontaneous resolution of liver fibrosis. The aim of this study was to investigate whether TIMP-1 altered spontaneous resolution of liver fibrosis in conjunction with matrix metalloproteinases (MMP) inhibition and hepatic stellate cell (HSC) activation. The livers of liver-targeted TIMP-1 transgenic (TIMP-Tg) and control hybrid (Cont) mice were harvested at 0, 3, 7, and 28 days following spontaneous recovery from CCl(4)-induced liver fibrosis. The extent of fibrosis resolution, MMP expression, alpha-smooth-muscle actin (alpha-SMA) positive cells, and procollagen-(I) messenger RNA (mRNA) in the liver were assessed at the respective periods in both groups. We also examined the effect of TIMP-1 on HSC apoptosis. The TIMP-Tg mice showed significantly attenuated resolution of spontaneous liver fibrosis compared with the Cont mice. The hydroxyproline content, number of alpha-SMA positive cells, and procollagen-(I) mRNA rapidly decreased with time in the Cont mice, whereas these markers were little changed in TIMP-Tg mice. The level of the active form of metalloproteinases-2 (MMP-2) in the TIMP-Tg mice was less than that in the Cont mice. TIMP-1 markedly decreased the nonparenchyma apoptotic cells in the liver fibrosis resolution model, and it also inhibited HSC apoptosis associated with suppression of caspase-3 activity in vitro. In conclusion, TIMP-1 significantly attenuated spontaneous resolution of liver fibrosis by the combination of a net reduction of the MMP activity and suppression of apoptosis in HSC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / genetics
  • Animals
  • Apoptosis / physiology
  • Collagen Type I / genetics
  • Collagenases / genetics
  • Collagenases / metabolism
  • Gene Expression Regulation, Enzymologic
  • Hydroxyproline / metabolism
  • In Vitro Techniques
  • Liver / metabolism*
  • Liver / pathology
  • Liver Cirrhosis / genetics
  • Liver Cirrhosis / metabolism*
  • Liver Cirrhosis / pathology
  • Matrix Metalloproteinase 13
  • Matrix Metalloproteinase 2 / genetics
  • Matrix Metalloproteinase 2 / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred CBA
  • Mice, Transgenic
  • RNA, Messenger / analysis
  • Tissue Inhibitor of Metalloproteinase-1 / genetics*
  • Tissue Inhibitor of Metalloproteinase-1 / metabolism*


  • Actins
  • Collagen Type I
  • RNA, Messenger
  • Tissue Inhibitor of Metalloproteinase-1
  • Collagenases
  • Matrix Metalloproteinase 13
  • Mmp13 protein, mouse
  • Matrix Metalloproteinase 2
  • Hydroxyproline