Simvastatin inhibits osteoclast differentiation by scavenging reactive oxygen species

• Published in: Experimental & molecular medicine 2011, 43(11), , pp.605-612
• Main Authors: Moon, Ho-Jin, Kim, Sung Eun, Yun, Young Pil, Hwang, Yu-Shik, Bang, Jae Beum, Park, Jae-Hong, Kwon, Il Keun
• Format: Article
• Language: English
• Subjects: Acid Phosphatase - genetics; Acid Phosphatase - metabolism; Animals; Anticholesteremic Agents - pharmacology; Biomedical and Life Sciences; Biomedicine; Blotting, Western; Cell Differentiation; Cells, Cultured; Hydrogen Peroxide - pharmacology; Isoenzymes - genetics; Isoenzymes - metabolism; Macrophages - cytology; Macrophages - drug effects; Macrophages - metabolism; Medical Biochemistry; Mice; Mitogen-Activated Protein Kinases - genetics; Mitogen-Activated Protein Kinases - metabolism; Molecular Medicine; NF-kappa B - genetics; NF-kappa B - metabolism; Original; Osteoclasts - cytology; Osteoclasts - drug effects; Osteoclasts - metabolism; RANK Ligand - metabolism; Reactive Oxygen Species - metabolism; Real-Time Polymerase Chain Reaction; RNA, Messenger - genetics; Simvastatin - pharmacology; Stem Cells; Tartrate-Resistant Acid Phosphatase; 생화학
• ISSN: 1226-3613; 2092-6413
• DOI: 10.3858/emm.2011.43.11.067

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 H 2 O 2 -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 H 2 O 2 -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.