MMP-13 deletion decreases profibrogenic molecules and attenuates N-nitrosodimethylamine-induced liver injury and fibrosis in mice

J Cell Mol Med. 2017 Dec;21(12):3821-3835. doi: 10.1111/jcmm.13304. Epub 2017 Aug 7.

Abstract

Connective tissue growth factor (CTGF) is involved in inflammation, pathogenesis and progression of liver fibrosis. Matrix metalloproteinase-13 (MMP-13) cleaves CTGF and releases several fragments, which are more potent than the parent molecule to induce fibrosis. The current study was aimed to elucidate the significance of MMP-13 and CTGF and their downstream effects in liver injury and fibrosis. Hepatic fibrosis was induced using intraperitoneal injections of N-nitrosodimethylamine (NDMA) in doses of 10 μg/g body weight on three consecutive days of each week over a period of 4 weeks in both wild-type (WT) and MMP-13 knockout mice. Administration of NDMA resulted in marked elevation of AST, ALT, TGF-β1 and hyaluronic acid in the serum and activation of stellate cells, massive necrosis, deposition of collagen fibres and increase in total collagen in the liver of WT mice with a significant decrease in MMP-13 knockout mice. Protein and mRNA levels of CTGF, TGF-β1, α-SMA and type I collagen and the levels of MMP-2, MMP-9 and cleaved products of CTGF were markedly increased in NDMA-treated WT mice compared to the MMP-13 knockout mice. Blocking of MMP-13 with CL-82198 in hepatic stellate cell cultures resulted in marked decrease of the staining intensity of CTGF as well as protein levels of full-length CTGF and its C-terminal fragments and active TGF-β1. The data demonstrate that MMP-13 and CTGF play a crucial role in modulation of fibrogenic mediators and promote hepatic fibrogenesis. Furthermore, the study suggests that blocking of MMP-13 and CTGF has potential therapeutic implications to arrest liver fibrosis.

Keywords: NDMA; MMP-13; N-nitrosodimethylamine; connective tissue growth factor; hepatic fibrosis.

MeSH terms

  • Actins / genetics
  • Actins / metabolism
  • Alanine Transaminase / blood
  • Animals
  • Aspartate Aminotransferases / blood
  • Chemical and Drug Induced Liver Injury / genetics
  • Chemical and Drug Induced Liver Injury / metabolism
  • Chemical and Drug Induced Liver Injury / pathology
  • Chemical and Drug Induced Liver Injury / prevention & control*
  • Collagen Type I / genetics
  • Collagen Type I / metabolism
  • Connective Tissue Growth Factor / genetics*
  • Connective Tissue Growth Factor / metabolism
  • Dimethylnitrosamine
  • Female
  • Gene Expression Regulation
  • Hepatic Stellate Cells / cytology
  • Hepatic Stellate Cells / drug effects
  • Hepatic Stellate Cells / metabolism
  • Hyaluronic Acid / blood
  • Injections, Intraperitoneal
  • Liver / metabolism
  • Liver / pathology
  • Liver Cirrhosis / chemically induced
  • Liver Cirrhosis / genetics
  • Liver Cirrhosis / metabolism
  • Liver Cirrhosis / prevention & control*
  • Male
  • Matrix Metalloproteinase 13 / deficiency
  • Matrix Metalloproteinase 13 / genetics*
  • Mice
  • Mice, Knockout
  • Primary Cell Culture
  • Proteolysis
  • Signal Transduction
  • Transforming Growth Factor beta1 / blood

Substances

  • Actins
  • CCN2 protein, mouse
  • Collagen Type I
  • Transforming Growth Factor beta1
  • alpha-smooth muscle actin, mouse
  • Connective Tissue Growth Factor
  • Hyaluronic Acid
  • Aspartate Aminotransferases
  • Alanine Transaminase
  • Matrix Metalloproteinase 13
  • Mmp13 protein, mouse
  • Dimethylnitrosamine

Associated data

  • GENBANK/BC006783
  • GENBANK/BC013738
  • GENBANK/X13297
  • GENBANK/BC059281
  • GENBANK/BC145810