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.

The Protective Role of Simvastatin on Methotrexate-Induced Bone Injury in Adult Albino Rat

“…Similarly, Moon et al proved that SIM acted as an osteoclastogenesis inhibitor by suppressing reactive oxygen species-mediated signaling pathways. Therefore, SIM has both anti-catabolic and anabolic effect on bone metabolism [43] . The potential positive effect of statins on bone formation can be explained by three mechanisms; (a) Promotion of osteogenesis.…”

Reactive oxygen species and oxidative stress in osteoclastogenesis, skeletal aging and bone diseases

“…Simvastatin, a 3-hydroxy-3 methylglutaryl coenzyme A (HMG Co-A) reductase inhibitor, used to treat high cholesterol, has also been shown to function as an antioxidant that can affect bone formation and resorption. Specifically, in the osteoclast, simvastatin administration led to a reduction in ROS levels and subsequent downregulation of osteoclastogenesis signaling pathways and osteoclast formation [62]. Many other compounds in the literature are suggested to improve conditions of excessive bone resorption through Importantly, although the aforementioned research appears promising with respect to using antioxidants to target ROS and improve bone quality, it is essential to remember that ROS is present throughout all cells of the body.…”

Alveolar process changes associated with administration of nucleos(t)ide analogue (sofosbuvir) in rat model

“…It was reported that ROS function as a signal mediator in osteoclast differentiation. 24,25 Cadmium (Cd) has been shown to induce caspaseindependent apoptosis through a mitochondria-ROS pathway. 26 Zhao et al investigated the effects of ROS in response to cadmium exposure on osteoblasts in rats.…”