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-κB
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)c1 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-1β,
tumor necrosis factor-α, 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.