Cardamonin inhibits osteoclastogenesis induced by tumor cells through interruption of the signaling pathway activated by receptor activator of NF-κB ligand

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 associated with human multiple myeloma, breast cancer, and prostate cancer and is usually treated with a bisphosphonate. Because of the numerous side effects of the currently available drugs, the search continues for safe and effective therapies for bone loss. Recently, receptor activator of NF-κB ligand (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 first isolated from grass cardamom (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. Cardamonin suppressed the differentiation of monocytes to osteoclasts in a dose-dependent and time-dependent manner. We also found that an NF-κB-specific inhibitory peptide blocked RANKL-induced osteoclastogenesis, indicating a direct link with NF-κB. Finally, osteoclastogenesis induced by human breast cancer cells or human multiple myeloma cells was 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 pathway.