Journal of Inflammation Research (Mar 2021)
BT2 Suppresses Human Monocytic-Endothelial Cell Adhesion, Bone Erosion and Inflammation
Abstract
Mei-Chun Yeh,1 Ben J Wu,1 Yue Li,1 Mina Elahy,1 Leonel Prado-Lourenco,1 Jim Sockler,2 Herman Lau,3 Ric O Day,4 Levon M Khachigian1 1Vascular Biology and Translational Research, School of Medical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, 2052, Australia; 2Statistical Operations & Programming, Datapharm Australia Pty Ltd, Drummoyne, NSW, 2047, Australia; 3BJC Health, Chatswood, NSW, 2067, Australia; 4Department of Clinical Pharmacology & Toxicology, Therapeutics Centre, St Vincent’s Hospital, UNSW Medicine and Health, Darlinghurst, NSW, 2010, AustraliaCorrespondence: Levon M KhachigianVascular Biology and Translational Research, School of Medical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, 2052, AustraliaTel +61 2 9385 2537Email [email protected]: Inflammation and bone erosion are processes key to the pathogenesis of rheumatoid arthritis, a systemic autoimmune disease causing progressive disability and pain, impacting around 1.3 million people in the United States alone. However, many patients do not respond sufficiently to existing therapies or benefit is not sustained and alternate therapeutic approaches are lacking. We recently identified the dibenzoxazepinone BT2, which inhibits ERK phosphorylation, from a high-throughput chemical screen and identified its ability to inhibit angiogenesis and vascular leakiness.Methods: Here we evaluated BT2 for potential anti-inflammatory activity in in vitro models of human monocytic-endothelial cell adhesion, monocytic cell extravasation and collagen antibody-induced arthritis in mice.Results: BT2 inhibits human monocytic cell adhesion to IL-1ß-treated human endothelial cells and inhibits monocytic transendothelial migration toward MCP-1. In mice rendered arthritic, single systemic administration of BT2 prevented footpad swelling, bone destruction and TRAP+ cells in the joints. BT2 suppressed inducible circulating levels of IL-1ß, IL-2 and IL-6 to normal levels without affecting levels of IL-4 or IL-10 among other cytokines. BT2 also inhibited the expression of pro-inflammatory adhesion molecules ICAM-1 and VCAM-1 in arthritic joints. There was no evidence of toxicity following intraperitoneal, gavage or intraarticular administration of BT2.Conclusion: BT2 is a novel small molecule inhibitor of joint inflammation, bone erosion, pro-inflammatory cytokine and adhesion molecule expression. This suggests the potential clinical utility of BT2 as a new anti-inflammatory agent.Keywords: inflammation, pathology, bone erosion, rheumatoid arthritis, dibenzoxazepinone
