The nitrosylated flurbiprofen derivative HCT1026 inhibits cytokine-induced signalling through a novel mechanism of action.
We have previously shown that the nitrosylated flurbiprofen derivative HCT1026 inhibits bone resorption, both in vivo and in vitro, and that its mechanism of action is independent of nitric oxide release and prostaglandin synthesis inhibition. Here we describe the effects of HCT1026 on osteoclast formation, activity, survival and cell signalling in vitro. HCT1026 strongly inhibited osteoclast formation, activity and survival in murine osteoclast cultures, whereas macrophages and osteoblasts were unaffected. HCT1026 induced osteoclast apoptosis, and this was partially prevented by increasing the concentration of receptor activator of nuclear factor kappa B ligand (RANKL). This suggests that HCT1026 inhibits bone resorption by inhibiting the effects of RANKL. In agreement with this we found that HCT1026 inhibited RANKL-induced activation of the nuclear factor kappa B (NFkappaB) and extracellular signal-regulated kinase (ERK) pathways in both osteoclast and macrophage cultures, whereas its parent compound flurbiprofen did not. In addition, HCT1026 also inhibited tumor necrosis factor (TNF)-, interleukin-1 (IL1)- and LPS-induced signalling, but not macrophage colony stimulating factor induced signalling. The pathways that are inhibited by HCT1026 all share a similar kinase complex upstream of the NFkappaB and ERK pathways, and this is the most likely target for the actions of HCT1026. Although the rationale for the modification of flurbiprofen with a nitric oxide donor group was to prevent gastro-intestinal toxicity, the resulting compound HCT1026 gained unexpected additional cytokine-inhibitory properties. As RANKL, TNF and IL1 are all important mediators of inflammation and joint destruction, compounds like HCT1026 could represent a novel class of anti-inflammatory compounds.
Idris
Aymen I
AI
Rheumatic Diseases Unit, Molecular Medicine Centre, University of Edinburgh, General Western Hospital, Edinburgh, UK.
Ralston
Stuart H
SH
van't Hof
Rob J
RJ
D000199:Actins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001862:Bone Resorption / Q000378:metabolism / Q000473:pathology; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005480:Flurbiprofen / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009603:Nitroso Compounds / Q000737:chemistry*; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D053245:RANK Ligand / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
D000199:Actins; D016207:Cytokines; D016328:NF-kappa B; D009603:Nitroso Compounds; D053245:RANK Ligand; C095631:nitroflurbiprofen; D005480:Flurbiprofen; D020928:Mitogen-Activated Protein Kinases