Neutralizing antibody against osteopontin attenuates non-alcoholic steatohepatitis in mice

Abstract

Previously, we reported that an extracellular matrix protein, osteopontin (OPN), is involved in various autoimmune diseases using a neutralizing polyclonal antibody against OPN generated in rabbits. However, the antibody cannot be used for long-term mouse models of chronic inflammatory disease because of the induction of antibodies against anti-OPN rabbit IgG. In this study, we generated a new antibody, anti-mouse OPN mouse IgG (35B6). 35B6 inhibited the cell adhesion of mouse and human OPN to Chinese Hamster Ovary (CHO) cells or CHO cells expressing α4 or α9 integrin. It was reported that OPN is highly expressed and has an important role in a chronic liver disease, non-alcoholic steatohepatitis (NASH). 35B6 injection twice a week for 8 weeks attenuated liver inflammation and fibrosis in a NASH mouse model, suggesting 35B6 is beneficial for the treatment of NASH. 35B6 was preferable to the rabbit anti-OPN antibody for investigating the in vivo function of OPN in mouse models of long-term disease. Keywords Osteopontin . Antibody . Non-alcoholic steatohepatitis in mice . Inflammation . Fibrosis Abbreviations CDAHFD 0.1% methionine on a high fat diet background col1a1 type I collagen α1 chain CHO Chinese Hamster Ovary ECM extracellular matrix HE hematoxylin-eosin HSC hepatic stellate cells RGD arginine-glycine-aspartate NAFLD non-alcoholic fatty liver disease NASH non-alcoholic steatohepatitis in mice OPN osteopontin SMA smooth muscle actin

Osteopontin Expression Identifies a Subset of Recruited Macrophages Distinct from Kupffer Cells in the Fatty Liver

“…This could suggest that hepatic LAMs drive the progression to NASH. Indeed, recent studies blocking osteopontin in mice models of NASH have suggested a protective effect ( Coombes et al., 2016 ; Honda et al., 2020 ; Kiefer et al., 2010 ). Unfortunately, to date, we do not have the tools to target this population specifically to address these questions, but generating these is an important aim for the future.…”

The interaction between cancer associated fibroblasts and tumor associated macrophages via the osteopontin pathway in the tumor microenvironment of hepatocellular carcinoma

“…In this study, we demonstrated the importance of cancer-TAM-CAF interactions via OPN for the first time. It has been suggested that OPN inhibitors might be useful in the prevention and treatment of hepatic inflammation and fibrosis in NASH [ 50 ]. Therefore, OPN might have potential as a new therapeutic target to inhibit cancer-CAF-TAM interactions in HCC.…”

Increased hepatic and circulating chemokine and osteopontin expression occurs early in human NAFLD development

“…In addition to a pro-fibrogenic role for OPN, it also has several pro-inflammatory properties targeting several innate immune cell populations including macrophages, neutrophils and natural killer cells [ 19 ]. A recent study in a murine NASH model demonstrated that antibodies targeting OPN not only attenuated fibrosis but also inflammation, suggesting that targeting OPN in the early stages of NAFLD may be effective in preventing the progression to NASH and fibrosis [ 21 ].…”