title: Simvastatin inhibits osteoclast differentiation by scavenging reactive oxygen species.
abstract: Osteoclasts, together with osteoblasts, control the amount of bone tissue and regulate bone remodeling. Osteoclast differentiation is an important factor related to the pathogenesis of bone-loss related diseases. Reactive oxygen species (ROS) acts as a signal mediator in osteoclast differentiation. Simvastatin, which inhibits 3-hydroxy-3-methylglutaryl coenzyme A, is a hypolipidemic drug which is known to affect bone metabolism and suppresses osteoclastogenesis induced by receptor activator of nuclear factor-κB ligand (RANKL). In this study, we analyzed whether simvastatin can inhibit RANKL-induced osteoclastogenesis through suppression of the subsequently formed ROS and investigated whether simvastatin can inhibit H2O2-induced signaling pathways in osteoclast differentiation. We found that simvastatin decreased expression of tartrate-resistant acid phosphatase (TRAP), a genetic marker of osteoclast differentiation, and inhibited intracellular ROS generation in RAW 264.7 cell lines. ROS generation activated NF-κB, protein kinases B (AKT), mitogen-activated protein kinases signaling pathways such as c-JUN N-terminal kinases, p38 MAP kinases as well as extracellular signal- regulated kinase. Simvastatin was found to suppress these H2O2-induced signaling pathways in osteoclastogenesis. Together, these results indicate that simvastatin acts as an osteoclastogenesis inhibitor through suppression of ROS-mediated signaling pathways. This indicates that simvastatin has potential usefulness for osteoporosis and pathological bone resorption.
authors.affiliation: Department of Maxillofacial Biomedical Engineering and Institute of Oral Biology.
authors.forename: Ho Jin
authors.initials: HJ
authors.lastname: Moon
authors.forename: Sung Eun
authors.initials: SE
authors.lastname: Kim
authors.forename: Young Pil
authors.initials: YP
authors.lastname: Yun
authors.forename: Yu Shik
authors.initials: YS
authors.lastname: Hwang
authors.forename: Jae Beum
authors.initials: JB
authors.lastname: Bang
authors.forename: Jae Hong
authors.initials: JH
authors.lastname: Park
authors.forename: Il Keun
authors.initials: IK
authors.lastname: Kwon
mesh_terms: D000135:Acid Phosphatase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002454:Cell Differentiation; D002478:Cells, Cultured; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D019821:Simvastatin / Q000494:pharmacology*; D000071681:Tartrate-Resistant Acid Phosphatase
chemical_list: D000924:Anticholesteremic Agents; D007527:Isoenzymes; D016328:NF-kappa B; D053245:RANK Ligand; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D019821:Simvastatin; D006861:Hydrogen Peroxide; D020928:Mitogen-Activated Protein Kinases; D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase