AK1 was increased by RANKL, while rhinacanthin C suppressed this effect. Rhinacanthin C may disrupt intracellular signal processing by targeting TRAF6TAK1 complex formation, thus impairing osteoclast differentiation. The direct targets of rhinacanthin C remain unknown. Recently, it was reported that -Vistin A and Norisoboldine inhibit osteoclast differentiation and prevent TRA6-TAK1 formation. Whether these natural compounds and rhinacanthin C target the same molecule will be the topic of future research. Consistent with its anti-osteoclastogenic effects in vitro, rhinacanthin C also inhibits RANKL-induced osteoclast formation and bone destruction in vivo. Furthermore, caldecrin inhibits LPS-stimulated osteoclast formation from BMMS and calvarial bone resorption. LPS is recognized by Toll-like receptor, which triggers recruitment of TRAF6 and TAK1, leading to activation of the NF-B pathway. TRAF6 knockout cells fail to respond to LPS stimulation. Rhinacanthin C might inhibit LPS-induced osteoclastogenesis by suppressing TRAF6-TAK1-NF-B signaling as it does in RANKL-induced osteoclastogenesis. These results and its reversible effects on osteoclast formation suggest the potential utility of rhinacanthin C in the treatment of conditions associated with abnormal bone lysis such as osteoporosis and inflammation-induced bone loss. Rhinacanthins are composed of naphthoquinone with variable side chains. Among the rhinacanthins, rhinacanthin C has the most potent anti-osteoclastogenic activity . Rhinacanthin C has a 2,6-dimethyl-2,6-octadienoic acid ester acid side chain. The relationship between side chain structure and anti-osteoclastogenic activity are a topic of future research. In summary, we have demonstrated that rhinacanthin C suppresses RANKL-stimulated 
TRAF6TAK1 complex formation and activation of PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19736993 the MAPK/NF-B/NFATc1 pathways, thereby suppressing expression of osteoclast marker proteins, finally resulting in impaired osteoclast differentiation and activation of bone resorption in cultured BMMs. Rhinacanthin C also suppresses LPS-induced osteoclast formation and bone destruction in vivo. The direct targets of rhinacanthin C that mediate its anti-osteogenic activity warrants further study. ~~ Recent evidence derived from both basic and clinical studies suggest that a pleiotropic effect, i.e., an effect other than that for which the agent was specifically intended, may be of value in the treatment of a variety of diseases. For example, erythromycin, a macrolide antibiotic, has been reported to be effective for the treatment of chronic airway diseases, such as diffuse bronchiolitis, bronchial asthma, and chronic sinusitis. These therapeutic benefits of erythromycin extend beyond its antibiotic 221877-54-9 web properties and the mechanism responsible for such pleiotropic effects includes the inhibition of neutrophil migration, the suppression of IL-8 production and Cl-secretion inhibitory action. Influenza virus infections are a serious public health problem that results in severe illness and death in high risk populations. The current therapeutic strategies for combating influenza virus infections involve directly targeting the influenza virus itself. However, it is well known that such infections often induce a lethal acute lung PubMed ID:http://www.ncbi.nlm.nih.gov/pubmed/19735871 injury, which largely contributes to the overproduction of reactive oxygen species and reactive nitrogen oxide species induced by complicated interactions that occur between the virus and host, including immunologic effects of t