Exp Mol Med.  2011 Nov;43(11):605-612. 10.3858/emm.2011.43.11.067.

Simvastatin inhibits osteoclast differentiation by scavenging reactive oxygen species

• Moon HJ
• Kim SE
• Yun YP
• Hwang YS
• Bang JB
• Park JH
• Kwon IK

• KMID: 1025163
• DOI: http://doi.org/10.3858/emm.2011.43.11.067

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-kappaB 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-kappaB, 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.

Keyword

bone resorption; mitogen-activated protein kinases; osteoclast; RANK ligand; reactive oxygen species; simvastatin

MeSH Terms

Acid Phosphatase/genetics/metabolism
Animals
Anticholesteremic Agents/*pharmacology
Blotting, Western
*Cell Differentiation
Cells, Cultured
Hydrogen Peroxide/pharmacology
Isoenzymes/genetics/metabolism
Macrophages/cytology/drug effects/metabolism
Mice
Mitogen-Activated Protein Kinases/genetics/metabolism
NF-kappa B/genetics/metabolism
Osteoclasts/*cytology/*drug effects/metabolism
RANK Ligand/metabolism
RNA, Messenger/genetics
Reactive Oxygen Species/*metabolism
Real-Time Polymerase Chain Reaction
Simvastatin/*pharmacology