title: RANKL signaling and osteoclastogenesis is negatively regulated by cardamonin.
abstract: 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.
authors.affiliation: Cytokine Research Laboratory, Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Bokyung
authors.initials: B
authors.lastname: Sung
authors.forename: Sahdeo
authors.initials: S
authors.lastname: Prasad
authors.forename: Vivek R
authors.initials: VR
authors.lastname: Yadav
authors.forename: Subash C
authors.initials: SC
authors.lastname: Gupta
authors.forename: Simone
authors.initials: S
authors.lastname: Reuter
authors.forename: Norio
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Akira
authors.initials: A
authors.lastname: Murakami
authors.forename: Bharat B
authors.initials: BB
authors.lastname: Aggarwal
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001862:Bone Resorption / Q000188:drug therapy*; D045744:Cell Line, Tumor; D047188:Chalcones / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D051379:Mice; D009000:Monocytes / Q000187:drug effects; D016328:NF-kappa B / Q000378:metabolism; D009841:Oligonucleotides / Q000235:genetics; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D053245:RANK Ligand / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D014343:Trypan Blue
chemical_list: D047188:Chalcones; D016328:NF-kappa B; D009841:Oligonucleotides; D053245:RANK Ligand; C505688:TNFSF11 protein, human; D051550:I-kappa B Kinase; C436747:cardamonin; D014343:Trypan Blue