Oncostatin M causes liver fibrosis by regulating cooperation between hepatic stellate cells and macrophages in mice

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-b 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). P atients with advanced liver fibrosis (LF) have poor prognosis because of impaired liver functions, adverse symptoms such as gastroesophageal varices and ascites, and hepatocellular carcinoma (HCC).(1,2) In the injured liver, activated hepatic stellate cells (HSCs) are the main producer of extracellular matrix (ECM), including type1 collagen, whereas the ECM can be degraded by various proteinases such as matrix metalloproteinases (MMPs). The balance between ECM production and degradation is

The oncostatin M‐stromal cell axis in health and disease

“…In contrast to these studies, virally mediated OSM expression was shown to protect rats from hepatic fibrosis in the dimethylnitrosamine model of liver damage, an effect that likely depended on OSM‐induced hepatocyte regeneration. However, repeated delivery of an OSM‐expression vector to the livers of healthy mice by hydrodynamic tail vein injection resulted in pronounced liver fibrosis that featured high levels of Timp1 and Col1a1 expression . Furthermore, Osm −/− mice were protected from liver fibrosis in the thioacetamide model of chronic hepatitis .…”

“…However, repeated delivery of an OSM‐expression vector to the livers of healthy mice by hydrodynamic tail vein injection resulted in pronounced liver fibrosis that featured high levels of Timp1 and Col1a1 expression . Furthermore, Osm −/− mice were protected from liver fibrosis in the thioacetamide model of chronic hepatitis . Notably, OSM‐mediated liver fibrosis was shown to be driven by both hepatic stellate cells, which expressed TIMP‐1 in response to OSM, and liver macrophages, which responded to OSM by expressing the fibrogenic mediators TGF‐β1 and PDGF‐B .…”

“…Furthermore, Osm −/− mice were protected from liver fibrosis in the thioacetamide model of chronic hepatitis . Notably, OSM‐mediated liver fibrosis was shown to be driven by both hepatic stellate cells, which expressed TIMP‐1 in response to OSM, and liver macrophages, which responded to OSM by expressing the fibrogenic mediators TGF‐β1 and PDGF‐B . Thus, the available evidence suggests that OSM can indeed promote fibrosis, but further studies of OSM loss of function in relevant fibrosis models are required to confirm this hypothesis.…”

“…OSMR, in contrast, is highly expressed by various nonhaematopoietic mesenchymal cells, including fibroblasts, endothelial cells, smooth muscle cells, osteoblasts and adipocytes, as well as hepatocytes, mesothelial cells, glial cells and epithelial cells from several organs . Whether OSMR is expressed at physiologically relevant levels by haematopoietic cells is less clear, but it may be expressed by monocytes following exposure to microbial stimuli or other activating signals, and possibly some macrophage populations . Because expression of LIFR is not generally associated with pathological processes, and studies of OSM typically report critical roles for OSMR (but not LIFR) in mediating OSM biology, this review will focus on biology related to the OSM‐OSMR axis unless otherwise noted.…”

In vivo affinity and target engagement in skin and blood in a first‐time‐in‐human study of an anti‐oncostatin M monoclonal antibody

“…Depending on the context, its functions include: activation of endothelium; induction of the acute phase response; induction of cellular proliferation and/or differentiation of cell types such as fibroblasts, epithelial cells and keratinocytes; modulation of erythropoiesis and megakaryopoiesis; inflammatory mediator release; and promotion of wound healing 4, 5, 6. OSM is implicated in a broad range of inflammatory and fibrotic diseases, including inflammatory bowel disease, liver fibrosis, idiopathic pulmonary fibrosis and systemic sclerosis (SSc) 4, 7, 8, 9, an autoimmune disease characterized by fibrosis of the skin and internal organs 10. As such, OSM is an important therapeutic target.…”