Michitaka Matsuda1, Shinya Tsurusaki1,2, Naoko Miyata1, Eiko Saijou3, Hitoshi Okochi1, Atsushi Miyajima3, Minoru Tanaka1,2. 1. Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan. 2. Laboratory of Stem Cell Regulation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan. 3. Laboratory of Cell Growth and Differentiation, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Tokyo, Japan.
Abstract
Fibrosis is an important wound-healing process in injured tissues, but excessive fibrosis is often observed in patients with chronic inflammation. Although oncostatin M (OSM) has been reported to play crucial roles for recovery from acute liver injury by inducing tissue inhibitor of metalloproteinase 1 (Timp1) expression, the role of OSM in chronic liver injury (CLI) is yet to be elucidated. Here, we show that OSM exerts powerful fibrogenic activity by regulating macrophage activation during CLI. Genetic ablation of the OSM gene alleviated fibrosis in a mouse model of chronic hepatitis. Conversely, continuous expression of OSM in a normal mouse liver by hydrodynamic tail vein injection (HTVi) induced severe fibrosis without necrotic damage of hepatocytes, indicating that OSM is involved in the fundamental process of liver fibrosis (LF) after hepatitis. In a primary coculture of hepatic stellate cells (HSCs) and hepatic macrophages (HMs), OSM up-regulated the expression of fibrogenic factors, such as transforming growth factor-β and platelet-derived growth factor in HMs, while inducing Timp1 expression in HSCs, suggesting the synergistic roles of OSM for collagen deposition in the liver. Fluorescence-activated cell sorting analyses using OSM-HTVi and OSM knockout mice have revealed that bone-marrow-derived monocyte/macrophage are responsive to OSM for profibrotic activation. Furthermore, depletion or blocking of HMs by administration of clodronate liposome or chemokine inhibitor prevented OSM-induced fibrosis. CONCLUSION: OSM plays a crucial role in LF by coordinating the phenotypic change of HMs and HSCs. Our data suggest that OSM is a promising therapeutic target for LF. (Hepatology 2018;67:296-312).
Fibrosis is an important wound-healing process in injured tissues, but excessive fibrosis is often observed in patients with chronic inflammation. Although oncostatin M (OSM) has been reported to play crucial roles for recovery from acute liver injury by inducing tissue inhibitor of metalloproteinase 1 (Timp1) expression, the role of OSM in chronic liver injury (CLI) is yet to be elucidated. Here, we show that OSM exerts powerful fibrogenic activity by regulating macrophage activation during CLI. Genetic ablation of the OSM gene alleviated fibrosis in a mouse model of chronic hepatitis. Conversely, continuous expression of OSM in a normal mouse liver by hydrodynamic tail vein injection (HTVi) induced severe fibrosis without necrotic damage of hepatocytes, indicating that OSM is involved in the fundamental process of liver fibrosis (LF) after hepatitis. In a primary coculture of hepatic stellate cells (HSCs) and hepatic macrophages (HMs), OSM up-regulated the expression of fibrogenic factors, such as transforming growth factor-β and platelet-derived growth factor in HMs, while inducing Timp1 expression in HSCs, suggesting the synergistic roles of OSM for collagen deposition in the liver. Fluorescence-activated cell sorting analyses using OSM-HTVi and OSM knockout mice have revealed that bone-marrow-derived monocyte/macrophage are responsive to OSM for profibrotic activation. Furthermore, depletion or blocking of HMs by administration of clodronate liposome or chemokine inhibitor prevented OSM-induced fibrosis. CONCLUSION: OSM plays a crucial role in LF by coordinating the phenotypic change of HMs and HSCs. Our data suggest that OSM is a promising therapeutic target for LF. (Hepatology 2018;67:296-312).
Authors: G Marden; Q Wan; J Wilks; K Nevin; M Feeney; N Wisniacki; M Trojanowski; A Bujor; L Stawski; M Trojanowska Journal: Arthritis Res Ther Date: 2020-07-31 Impact factor: 5.156