BT2 Suppresses Human Monocytic-Endothelial Cell Adhesion, Bone Erosion and Inflammation

Abstract

Introduction: 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.

Label-free LC–MS/MS proteomics analyses reveal proteomic changes in oxidative stress and the SOD antioxidant strategy in TM cells

“…When ICAM-1 levels increase, JNK is activated, leading to internalization of VE-cadherin, disruption of cell junctions and impairment of cell barrier function [ 21 ]. In addition, ICAM-1 can activate monocytes to enhance the stimulation and transmigration of inflammatory cells into the ECM [ 24 , 25 ], substantially increasing apoptosis. In our study, ICAM-1 levels were significantly increased, and ICAM-1 was the major protein in the TNF signaling pathway, NF-kB signaling pathway and AGE-RAGE signaling pathway in diabetic complications.…”

Label-Free LC-MS/MS Proteomics Analyses Reveal Proteomic Changes In Oxidative Stress And The SOD Antioxidant Strategy In TM Cells.

“…In endothelial cells, ICAM-1 often plays a key role in mediating rm adhesion of leukocytes and participates in many physiological processes [21 . It has been reported that ICAM-1 can regulate endothelial cell permeability in healthy and in amed tissue [22,23 . When ICAM-1 levels increase, JNK is activated, leading to internalization of VE-cadherin, disruption of cell junctions and impairment of cell barrier function [21 . In addition, ICAM-1 can activate monocytes to enhance the stimulation and transmigration of in ammatory cells into the ECM) [24,25 , substantially increasing apoptosis. In our study, ICAM-1 levels were signi cantly increased, and ICAM-1 was the major protein in the TNF signaling pathway, NF-kB signaling pathway and AGE-RAGE signaling pathway in diabetic complications.…”

Emerging therapeutic strategies for unmet need in neovascular age-related macular degeneration

“…We recently identified BT2, a dibenzoxazepinone that can suppress not only VEGF-A, but also p-ERK, MCP-1, ICAM-1, VCAM-1, IL-1β and IL-6 among a range of other pro-angiogenic and pro-inflammatory mediators relevant to nAMD [ 191 , 192 ]. This includes transcription factors ( e.g., Egr-1, c-Rel/NF-κB, KLF) and pro-angiogenic chemokines ( e.g., CXCL1, CXCL3, CXCL8, CCL20).…”