title: Bortezomib Inhibits Osteoclastogenesis and Porphyromonas gingivalis Lipopolysaccharide-induced Alveolar Bone Resorption.
abstract: Healthy bone is maintained by the coordinated activities of osteoblast-mediated bone formation and osteoclast-dependent bone resorption. Pathologic conditions such as hormonal imbalance and inflammation cause increased osteoclastogenesis resulting in osteoporosis, rheumatoid arthritis, and periodontitis. Bortezomib is novel antimyeloma agent that has a direct beneficial effect on bone formation. However, the role of bortezomib in osteoclastogenesis and underlying mechanisms remains to be fully comprehended. In the present study, we show that bortezomib directly inhibited the receptor activator of nuclear factor κB ligand (RANKL)- and lipopolysaccharide-dependent osteoclast differentiation. Interestingly, the bortezomib-mediated inhibition of osteoclastogenesis was transient, since the removal of bortezomib from culture completely restored osteoclast differentiation. Bortezomib impeded the induction and nuclear localization of nuclear factor of activated T cells, cytoplasmic 1 and reduced both macrophage colony-stimulating factor- and RANKL-induced extracellular-signal-regulated kinase (ERK) phosphorylation. In a mouse model of periodontitis, bortezomib prevented alveolar bone erosion induced by Porphyromonas gingivalis lipopolysaccharide. These data not only suggest a previously unappreciated mechanism by which bortezomib regulates bone resorption but also propose novel applications of bortezomib beyond its use as an antimyeloma agent.
authors.affiliation: Department of Periodontology, School of Dentistry, Kyungpook National University, Daegu, Korea.
authors.forename: Y-G
authors.initials: YG
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, School of Dentistry, Kyungpook National University, Daegu, Korea.
authors.forename: J H
authors.initials: JH
authors.lastname: Kang
authors.affiliation: Department of Biochemistry, School of Dentistry, Kyungpook National University, Daegu, Korea.
authors.forename: H J
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Physiology, School of Dentistry, Pusan National University, Yangsan, Korea.
authors.forename: H J
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Cell and Developmental Biology, School of Dentistry, Seoul National University, Seoul, Korea.
authors.forename: H-H
authors.initials: HH
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, School of Dentistry, Kyungpook National University, Daegu, Korea.
authors.forename: J-Y
authors.initials: JY
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, School of Dentistry, Kyungpook National University, Daegu, Korea ylee@knu.ac.kr.
authors.forename: Y
authors.initials: Y
authors.lastname: Lee
mesh_terms: D000539:Alveolar Process / Q000187:drug effects*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000187:drug effects*; D016966:Porphyromonas gingivalis / Q000187:drug effects* / Q000472:pathogenicity; D011719:Pyrazines / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D008070:Lipopolysaccharides; D011719:Pyrazines; D000069286:Bortezomib
keywords: ERK; NFATc1; differentiation; fusion; osteoclast; periodontitis