Molecular Medicine Centre, Institute for Genetics and Molecular Medicine, University of Edinburgh, General Western Hospital, Edinburgh, UK.
School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Aberdeen, UK.
Ann Rheum Dis. 2015 Jan;74(1):220-6. doi: 10.1136/annrheumdis-2013-203700. Epub 2013 Oct 4.
Inflammatory joint diseases such as rheumatoid arthritis are associated with local bone erosions and systemic bone loss, mediated by increased osteoclastic activity. The receptor activator of nuclear factor (NF) κB ligand (RANKL) plays a key role in mediating inflammation-induced bone loss, whereas tumour necrosis factor (TNF) plays a central role in the inflammatory process. Here we tested whether a recently identified class of small molecule inhibitors of RANKL signalling (ABD compounds) also affect TNF signalling and whether these compounds inhibit inflammation in an animal model of rheumatoid arthritis.
The inhibitory effects of the ABD compounds on TNF-induced signalling were tested in mouse macrophage cultures by western blotting and in an NFκB luciferase-reporter cell line. The anti-inflammatory effects of the compounds were tested in the mouse collagen-induced arthritis model of rheumatoid arthritis.
The ABD compounds ABD328 and ABD345 both inhibited TNF-induced activation of the NFκB pathway and the extracellular signal-regulated kinase (ERK) and Jun kinase (JNK) mitogen activated protein kinases (MAPKs). When tested in the mouse collagen-induced arthritis model of rheumatoid arthritis, the compounds suppressed inflammatory arthritis, inhibited joint destruction and prevented systemic bone loss. Furthermore, one of the compounds (ABD328) showed oral activity.
Here we describe a novel class of small molecule compounds that inhibit both RANKL- and TNF-induced NFκB and MAPK signalling in osteoclasts and macrophages, and inflammation and bone destruction in a mouse model of rheumatoid arthritis. These novel compounds therefore represent a promising new class of treatments for inflammatory diseases, such as rheumatoid arthritis.
类风湿关节炎等炎性关节疾病与局部骨侵蚀和全身性骨质流失有关，这是由破骨细胞活性增加介导的。核因子（NF）κB 配体（RANKL）受体激活剂在介导炎症诱导的骨质流失方面起着关键作用，而肿瘤坏死因子（TNF）在炎症过程中起着核心作用。在这里，我们测试了最近发现的一类 RANKL 信号小分子抑制剂（ABD 化合物）是否也会影响 TNF 信号，以及这些化合物是否会在类风湿关节炎的动物模型中抑制炎症。
通过 Western blot 在小鼠巨噬细胞培养物中以及在 NFκB 荧光素酶报告细胞系中测试 ABD 化合物对 TNF 诱导的信号的抑制作用。在类风湿关节炎的小鼠胶原诱导关节炎模型中测试化合物的抗炎作用。
ABD 化合物 ABD328 和 ABD345 均抑制 TNF 诱导的 NFκB 途径以及细胞外信号调节激酶（ERK）和 Jun 激酶（JNK）丝裂原激活蛋白激酶（MAPKs）的激活。在类风湿关节炎的小鼠胶原诱导关节炎模型中测试时，这些化合物抑制了炎症性关节炎，抑制了关节破坏并防止了全身性骨质流失。此外，其中一种化合物（ABD328）具有口服活性。
在这里，我们描述了一类新型小分子化合物，它们可抑制破骨细胞和巨噬细胞中 RANKL 和 TNF 诱导的 NFκB 和 MAPK 信号，以及类风湿关节炎小鼠模型中的炎症和骨破坏。因此，这些新型化合物代表了一种有前途的炎性疾病（如类风湿关节炎）的新治疗方法。
