Aminocoumarins inhibit osteoclast differentiation and bone resorption via downregulation of nuclear factor of activated T cells c1

Abstract

Aminocoumarins, such as coumermycin A1 and novobiocin, are natural products of streptomycetes. They are potent inhibitors of bacterial DNA gyrase and are used to suppress the growth of bacteria in inflammatory diseases. However, their effect in osteoclastogenesis has not been investigated. In this study, using mouse bone-marrow-derived macrophages (BMMs), we showed that coumermycin A1 and novobiocin suppressed receptor activator of nuclear factor-kappa B ligand (RANKL)-induced osteoclast formation. The inhibitory effect of coumermycin A1 was associated with impaired activation of multiple signaling events downstream of RANK, including extracellular signal-regulated kinase, p38, and c-Jun terminal kinase phosphorylation, followed by decreased c-Fos and nuclear factor of activated T cells (NFAT)cl expression. Ectopic overexpression of a constitutively active form of NFATc1 completely rescued the anti-osteoclastogenic effect of coumermycin A1, suggesting that the anti-osteoclastogenic effect of coumermycin A1 was mainly attributable to reduction in NFATc1 expression. Coumermycin A1 also abrogated RANKL-induced expression of interleukin-1 beta, tumor necrosis factor-a, and inducible nitric oxide synthase in mouse BMMs. Consistent with the in vitro anti-osteoclastogenic effect, the aminocoumarin suppressed lipopolysaccharide-induced osteoclast formation and bone loss in in vivo mouse experiments. Taken together, our data demonstrate that aminocoumarins inhibit osteoclast formation and bone resorption, and comprise a potential therapeutic strategy for treating bone destructive diseases. (C) 2012 Elsevier Inc. All rights reserved.