Hepatoprotective Effect of MMP-19 Deficiency in a Mouse Model of Chronic Liver Fibrosis

Abstract

Liver fibrosis is characterized by the deposition and increased turnover of extracellular matrix. This process is controlled by matrix metalloproteinases (MMPs), whose expression and activity dynamically change during injury progression. MMP-19, one of the most widely expressed MMPs, is highly expressed in liver; however, its contribution to liver pathology is unknown. The aim of this study was to elucidate the role of MMP-19 during the development and resolution of fibrosis by comparing the response of MMP-19-deficient (MMP19KO) and wild-type mice upon chronic liver CCl4-intoxication. We show that loss of MMP-19 was beneficial during liver injury, as plasma ALT and AST levels, deposition of fibrillar collagen, and phosphorylation of SMAD3, a TGF-ß1 signaling molecule, were all significantly lower in MMP19KO mice. The ameliorated course of the disease in MMP19KO mice likely results from a slower rate of basement membrane destruction and ECM remodeling as the knockout mice maintained significantly higher levels of type IV collagen and lower expression and activation of MMP-2 after 4 weeks of CCl4-intoxication. Hastened liver regeneration in MMP19KO mice was associated with slightly higher IGF-1 mRNA expression, slightly increased phosphorylation of Akt kinase, decreased TGF-ß1 mRNA levels and significantly reduced SMAD3 phosphorylation. In addition, primary hepatocytes isolated from MMP19KO mice showed impaired responsiveness towards TGF-ß1 stimulation, resulting in lower expression of Snail1 and vimentin mRNA. Thus, MMP-19-deficiency improves the development of hepatic fibrosis through the diminished replacement of physiological extracellular matrix with fibrotic deposits in the beginning of the injury, leading to subsequent changes in TGF-ß and IGF-1 signaling pathways.

Biochemical and Biological Attributes of Matrix Metalloproteinases

“…MMP-19-deficiency may decrease the development of hepatic fibrosis through decreased replacement of physiological ECM with fibrotic deposits in the beginning of the injury. 182 …”

Matrix Metalloproteinases as Therapeutic Targets for Idiopathic Pulmonary Fibrosis

“…MMP-19 may also mediate its protective activities by regulating adaptive immune responses as: 1) unchallenged Mmp19 -/mice have impaired thymocyte maturation and T cell-mediated contact hypersensitivity (88); and 2) reduced expression of T cell co-stimulatory molecules predicts decreased transplant-free survival in IPF patients (89). However, MMP-19 has pro-fibrotic activities in mice with hepatic fibrosis (90). Thus, the activities of MMP-19 in regulating fibrotic responses to injury depend on the site of injury and the inciting agent.…”

Metalloproteinases in liver fibrosis: current insights

“…MMP-19 deficiency causes fibrosis exacerbation in chronic fibrosis models induced by CCL 4 application. 65 MMP-12 is also involved in the regulation of fibrotic matrix processing as the oral 65 Chung et al, 126 Jiang et al, 127 Marsillach et al 128 Thioacetamide MMP-2, MMP-12, TIMP-1, TIMP-2…”

“…68 MMP-19 seems to be involved in TGFβ signaling as well, as MMP-19 knockout hepatocytes exhibit lower response to the cytokine. 65 Also, MT1-MMP participates in the regulation of fibrosis progression as it cleaves intramolecular RGD motifs of collagen produced by activated HSCs and thus controls aVβ1 activation, providing a survival signal via PI3K/AKT/IκB. 69 During the entire progress of liver fibrosis, the expression of main inhibitor of MMPs, TIMP-1, is increased to regulate the elevated MMP activity.…”