Identification of small molecule inhibitors of RANKL and TNF signalling as anti-inflammatory and antiresorptive agents in mice

Abstract

Introduction 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. Methods 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. Results 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 collageninduced 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. Conclusions Here we describe a novel class of small molecule compounds that inhibit both RANKL-and TNFinduced 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.

Blood-induced bone loss in murine hemophilic arthropathy is prevented by blocking the iRhom2/ADAM17/TNF-α pathway

“…Moreover, anti-TNF-a treatment also helps to prevent bone resorption in patients with RA and inflammatory bowel disease 30,31,70,71 and in inflammatory arthritis models in mice. 72,73 Interestingly, unilateral osteopenia adjacent to the injured knee can occur in patients following ACL injury, 67,74 raising questions about a possible role for TNF-a in this process. In light of the significant variability in the development of HA in hemophiliacs with similar severities of factor deficiency, 4 it will be interesting to determine whether polymorphisms in the iRhom2/ADAM17/TNF-a pathway or other inflammatory cytokines might contribute to this variability.…”

Modified Salicylanilide and 3-Phenyl-2H-benzo[e][1,3]oxazine-2,4(3H)-dione Derivatives as Novel Inhibitors of Osteoclast Differentiation and Bone Resorption

“…For each series, there are six different member compounds distinguished by the substituent groups of benzene rings A and B (Scheme ). Furthermore, since some biphenyl-containing derivatives inhibit osteoclastic bone resorption by inducing osteoclast apoptosis and inhibiting osteoclast formation, ,, we were particularly interested in replacing the iodine atom in 5a and 6a with a phenyl group, affording compounds 7a – 12a . To characterize the biological activities of these synthetic compounds, we evaluated their effects on RANKL-induced osteoclastogenesis from osteoclast precursor cells (RAW264.7) by the TRAP stain assay.…”

Novel inhibitors of RANKL-induced osteoclastogenesis: Design, synthesis, and biological evaluation of 6-(2,4-difluorophenyl)-3-phenyl-2H-benzo[e][1,3]oxazine-2,4(3H)-diones

“…Recently, van't Hof developed a series of biphenyl-based derivatives including the 2 0 ,4 0 -difluorobiphenyl pharmacophore, as inhibitors of the RANKL-induced osteoclastogenesis which exhibited anti-resorptive effects in vitro and in vivo. [43][44][45][46][47][48][49] These observations along with our previous promising results initiated quest for the development of a new class of anti-resorptive agents.…”

“…1). 43 In our previous work, we developed a salicylanilide-derived synthetic http small molecule (NDMC101) that not only inhibited the RANKL-induced osteoclastogenesis by suppressing NFATc1 and NF-jB activity, but also significantly reduced the number of TRAP-staining osteoclasts at sites of articular bone erosions in collagen-induced arthritis (CIA) mice. 41 On the basis of these findings, the lead structure of NDMC101 can be considered as an osteoclastogenesis inhibitor that warrants further lead optimization.…”