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

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

Author information

1
Department of Medicine, Division of Molecular Medicine, College of Physicians and Surgeons, Columbia University, New York, NY, USA.
2
Department of Hepatology, Kanazawa Medical University, Uchinada, Ishikawa, Japan.

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

PMID:
28782260
PMCID:
PMC5706575
DOI:
10.1111/jcmm.13304
[Indexed for MEDLINE]
Free PMC Article

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