Simvastatin inhibits osteoclast differentiation induced by bone morphogenetic protein-2 and RANKL through regulating MAPK, AKT and Src signaling

Yamashita, Misuzu; Otsuka, Fumio; Mukai, Tomoyuki; Yamanaka, Ryutaro; Otani, Hiroyuki; Matsumoto, Yoshinori; Nakamura, Eri; Takano, Mariko; Sada, Ken‐ei; Makino, Hírofumi

doi:10.1016/j.regpep.2010.03.003

Cited by 77 publications

(56 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This ROS production during RANKL-simulated osteoclast differentiation decreased distinctly when the RAW 264.7 cells were co-treated with simvastatin. Previous studies have reported on the inhibitory function of simvastatin on osteoclast differentiation by blocking the RANKL-induced signaling pathway (Ahn et al, 2008;Yamashita et al, 2010). It has also been reported that simvastatin has antioxidant activity (Giroux et al, 1993;Girona et al, 1999;Mason, 1999;Tomás et al, 2000;Davignon et al, 2004).…”

Section: Discussionmentioning

confidence: 98%

“…To date, various drugs have been developed and applied to treat such bone loss related diseases. Simvastatin is known to be one of these drugs used to suppress bone resorption by inhibiting osteoclastogenesis (Yamashita et al, 2010). However, the underlying biological mechanism of simvastatin's inhibitory effect on osteoclast differentiation has yet to be elucidated.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Simvastatin inhibits osteoclast differentiation by scavenging reactive oxygen species

et al. 2011

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Simvastatin inhibits osteoclast differentiation by scavenging reactive oxygen species

et al. 2011

View full text Add to dashboard Cite

show abstract

“…Since AMPK was recently shown to promote b-catenin transcription through phosphorylation of class IIa histone deacetylase 5 , it is therefore probable that AMPK regulates osteoblast differentiation through crosstalk with the Wnt/b-catenin pathway. Another pathway that is important for both osteoblast differentiation and osteoclastic bone resorption is the mevalonate pathway (Kanazawa et al 2009a, Dunford 2010, Yamashita et al 2010). This pathway is required for the prenylation of regulatory proteins such as Ras and Rho GTPases that play a pivotal role in the regulation of numerous key cellular processes.…”

Section: Possible Targets and Metabolic Pathways Regulated By Ampk Inmentioning

confidence: 99%

AMP-activated protein kinase pathway and bone metabolism

Jeyabalan

Shah²,

Viollet³

et al. 2011

Journal of Endocrinology

View full text Add to dashboard Cite

There is increasing evidence that osteoporosis, similarly to obesity and diabetes, could be another disorder of energy metabolism. AMP-activated protein kinase (AMPK) has emerged over the last decade as a key sensing mechanism in the regulation of cellular energy homeostasis and is an essential mediator of the central and peripheral effects of many hormones on the metabolism of appetite, fat and glucose. Novel work demonstrates that the AMPK signaling pathway also plays a role in bone physiology. Activation of AMPK promotes bone formation in vitro and the deletion of a or b subunit of AMPK decreases bone mass in mice. Furthermore, AMPK activity in bone cells is regulated by the same hormones that regulate food intake and energy expenditure through AMPK activation in the brain and peripheral tissues. AMPK is also activated by antidiabetic drugs such as metformin and thiazolidinediones (TZDs), which also impact on skeletal metabolism. Interestingly, TZDs have detrimental skeletal side effects, causing bone loss and increasing the risk of fractures, although the role of AMPK mediation is still unclear. These data are presented in this review that also discusses the potential roles of AMPK in bone as well as the possibility for AMPK to be a future therapeutic target for intervention in osteoporosis.

show abstract

“…Drugs called statins have been used for over 30 years to treat hyperlipidemia and arteriosclerosis. These drugs may stimulate the expression of BMP2 and prevent the prenylation of some GTPase proteins 6,7 .…”

Section: Introductionmentioning

confidence: 99%

“…Statins also reduce bone resorption and therefore inhibit farnesylpyrophosphate (geranilgeranilpirofosfato), which is essential for cell differentiation and the function of osteoclasts 6 .…”

Section: Introductionmentioning

confidence: 99%

The effect of simvastatin on the regeneration of surgical cavities in the femurs of rabbits

Rosselli

Martins

et al. 2014

Acta Cir. Bras.

View full text Add to dashboard Cite

PURPOSE:To evaluate the effect of a local application of simvastatin gel in repairing bone defects in the femurs of rabbits. METHODS:Two standard surgical cavities were created in the femoral epiphysis of 18 rabbits. In the simvastatin group (SG), the cavities were filled with a collagen sponge soaked in 0.5 ml of a simvastatin (1 mg) gel, and the cavities were covered with a biological membrane. The bone cavities in the second group (control group) were filled with a blood clot and covered with a biological membrane.On the 7 th, 21st and 42 nd days, six animals in each group were euthanized, and the femurs were subject to histological evaluation (vascularity, fibrosis, reactive bone formation, osteoblasts, and osteoclasts) and immunohistochemical (anti-VEGF and anti-osteocalcin) analysis.The results were analyzed using a Wilcoxon test (p<0.05). RESULTS:There were significant differences between the two groups: the SG had greater scores in comparison with the CG in terms of the degree of vascularity on the 7t h and the 21st days, fibrosis on the 21 st day, bone formation reaction on the 21 st and the 42 nd days and the number of osteoblasts and osteoclasts on the 42 nd day. The immunohistochemical expression was also greater for osteocalcin and VEGF on the 7 th, 21st and 42 nd days. CONCLUSION:Surgical defects created in rabbit femurs were treated locally with simvastatin gel to stimulate bone repair, which promoted an ameliorative effect in the morphological and immunohistochemical markers of bone regeneration.

show abstract

Simvastatin inhibits osteoclast differentiation induced by bone morphogenetic protein-2 and RANKL through regulating MAPK, AKT and Src signaling

Cited by 77 publications

References 52 publications

Simvastatin inhibits osteoclast differentiation by scavenging reactive oxygen species

Simvastatin inhibits osteoclast differentiation by scavenging reactive oxygen species

AMP-activated protein kinase pathway and bone metabolism

The effect of simvastatin on the regeneration of surgical cavities in the femurs of rabbits

Contact Info

Product

Resources

About