Zerumbone abolishes RaNKL-induced NF-κB activation, inhibits osteoclastogenesis, and suppresses human breast cancer-induced bone loss in athymic nude mice

Receptor activator of nuclear factor-κB(NF-κB) ligand (RANKL) has emerged as a major mediator of bone resorption, commonly associated with cancer and other chronic inflam-matory diseases. Inhibitors of RANKL signaling thus have potential in preventing bone loss. In the present report, the potential of zerumbone, a sesquiterpene derived from subtropical ginger, to modulate osteoclastogenesis induced byRANKL and breast cancer was examined. We found that zerumbone inhibited RANKL-induced NF-κB activation in mouse monocyte, an osteoclast precursor cell, through inhibition of activation of IκBo kinase, IκBα phosphorylation, and IκBα degradation. Zerumbone also suppressed RANKL-induced differentiation of these cells to osteoclasts. This sesquiterpene also inhibited the osteoclast formation induced byhuman breast tumor cells and bymultiple myeloma cells. Finally, we examined whether zerumbone could prevent human breast cancer-induced bone loss in animals. We found that zerumbone decreased osteolysis in a dose-dependent manner in MDA-MB-231 breast cancer tumor-bearing athymic nude mice. These results indicate that zerumbone is an effective blocker of RANKL-induced NF-κB activation and of osteoclastogenesis induced byRANKL and tumor cells, suggesting its potential as a therapeutic agent for osteoporosis and cancer-associated bone loss.