Yeh Mei-Chun, Wu Ben J, Li Yue, Elahy Mina, Prado-Lourenco Leonel, Sockler Jim, Lau Herman, Day Ric O, Khachigian Levon M
Vascular Biology and Translational Research, School of Medical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, 2052, Australia.
Statistical Operations & Programming, Datapharm Australia Pty Ltd, Drummoyne, NSW, 2047, Australia.
J Inflamm Res. 2021 Mar 23;14:1019-1028. doi: 10.2147/JIR.S296676. eCollection 2021.
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.
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.
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.
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.
炎症和骨侵蚀是类风湿性关节炎发病机制的关键过程，类风湿性关节炎是一种全身性自身免疫性疾病，会导致进行性残疾和疼痛，仅在美国就影响约130万人。然而，许多患者对现有疗法反应不足，或者疗效无法持续，且缺乏替代治疗方法。我们最近从高通量化学筛选中鉴定出二苯并恶唑酮BT2，它能抑制细胞外信号调节激酶（ERK）磷酸化，并确定了其抑制血管生成和血管渗漏的能力。
在此，我们在人单核细胞-内皮细胞粘附、单核细胞外渗的体外模型以及小鼠胶原抗体诱导的关节炎模型中评估了BT2的潜在抗炎活性。
BT2抑制人单核细胞与白细胞介素-1β（IL-1β）处理的人内皮细胞的粘附，并抑制单核细胞向单核细胞趋化蛋白-1（MCP-1）的跨内皮迁移。在患有关节炎的小鼠中，单次全身给药BT2可预防足垫肿胀、骨破坏和关节中的抗酒石酸酸性磷酸酶（TRAP）细胞。BT2将白细胞介素-1β、白细胞介素-2和白细胞介素-6的诱导循环水平抑制至正常水平，而不影响白细胞介素-4或白细胞介素-10等其他细胞因子的水平。BT2还抑制关节炎关节中促炎粘附分子细胞间粘附分子-1（ICAM-1）和血管细胞粘附分子-1（VCAM-1）的表达。腹腔内、灌胃或关节内给予BT2后均无毒性证据。
BT2是一种新型的关节炎症、骨侵蚀、促炎细胞因子和粘附分子表达的小分子抑制剂。这表明BT2作为一种新型抗炎药具有潜在的临床应用价值。
