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

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.

• Authors: Joseph George, Mikihiro Tsutsumi, Mutsumi Tsuchishima
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 21 Issue 12 Pg. 3821-3835 (Dec 2017) ISSN: 1582-4934 [Electronic] England
• PMID: 28782260 (Publication Type: Journal Article)
• Copyright: © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Chemical References

• 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

Topics

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