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.
Highlights
Hepatic fibrosis is a result of an abnormal wound healing in response to chronic liver injury from various causes [1, 2]
We have demonstrated that loss of Matrix metalloproteinase-13 (MMP-13) attenuates NDMA-induced liver injury and fibrosis in a mouse model, and suggested that Matrix metalloproteinases (MMPs)-13 is involved in the accelerated inflammation by overexpression and activation of Connective tissue growth factor (CTGF) in the impaired liver
This study provided the data that MMP-13 has a role in the expression of pro-inflammatory mediators such as tumour necrosis factor-a (TNF-a) and Chemokine (C-C motif) ligand 2 (CCL2), which modulate the initial liver damage in their model
Summary
Hepatic fibrosis is a result of an abnormal wound healing in response to chronic liver injury from various causes [1, 2]. The chronic hepatocyte injury leads to the activation of resting hepatic stellate cells (HSCs) into myofibroblast-like cells with the characteristic expression of smooth muscle actin filaments [5, 6]. N-Nitrosodimethylamine (NDMA), known as dimethylnitrosamine (DMN), is a by-product of several industrial processes and a suspected human carcinogen and highly toxic to the liver. It was Matrix metalloproteinases (MMPs) are a gene family of zinc- and calcium-dependent endopeptidases that are capable of degrading extracellular matrix (ECM) components including all forms of native collagens, and play a key role in remodelling the ECM in both physiological and pathological conditions [14, 15]. Mice and rats do not possess a homologue to a 2017 The Authors
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