Bone loss/resorption or
osteoporosis is a disease that is accelerated with aging and age-associated
chronic diseases such as
cancer. Bone loss has been linked with human
multiple myeloma,
breast cancer, and
prostate cancer and is usually treated with
bisphosphonates, and recently approved
denosumab, an antibody against receptor activator of NF-κB
ligand (RANKL). Because of the numerous side effects of the currently available drugs, the search continues for safe and effective
therapies for bone loss. RANKL, a member of the TNF superfamily, has emerged as a major mediator of bone loss via activation of osteoclastogenesis. We have identified
cardamonin, a
chalcone isolated from Alpinia katsumadai Hayata that can affect osteoclastogenesis through modulation of RANKL. We found that treatment of monocytes with
cardamonin suppressed RANKL-induced NF-κB activation and this suppression correlated with inhibition of IκBα
kinase and of phosphorylation and degradation of IκBα, an inhibitor of NF-κB. Furthermore,
cardamonin also downregulated RANKL-induced phosphorylation of MAPK including ERK and
p38 MAPK.
Cardamonin suppressed the RANKL-induced differentiation of monocytes to osteoclasts in a dose-dependent and time-dependent manner. We also found that an inhibitor of NF-κB essential modulator (NEMO) blocked RANKL-induced osteoclastogenesis, indicating a direct link with NF-κB. Finally, osteoclastogenesis induced by human
breast cancer cells or human
multiple myeloma cells were completely suppressed by
cardamonin. Collectively, our results indicate that
cardamonin suppresses osteoclastogenesis induced by RANKL and
tumor cells by suppressing activation of the NF-κB and MAPK pathway.