Department of Maxillofacial Biomedical Engineering and Institute of Oral Biology.
Exp Mol Med. 2011 Nov 30;43(11):605-12. 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 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.
破骨细胞与成骨细胞一起控制骨组织的量并调节骨重塑。破骨细胞分化是与骨丢失相关疾病发病机制相关的重要因素。活性氧 (ROS) 作为破骨细胞分化的信号介质发挥作用。辛伐他汀抑制 3-羟基-3-甲基戊二酰基辅酶 A，是一种降脂药物，已知其可影响骨代谢并抑制核因子-κB 受体激活剂配体 (RANKL) 诱导的破骨细胞生成。在这项研究中，我们分析了辛伐他汀是否可以通过抑制随后形成的 ROS 来抑制 RANKL 诱导的破骨细胞生成，并研究了辛伐他汀是否可以抑制 H2O2 诱导的破骨细胞分化中的信号通路。我们发现辛伐他汀降低了 RAW 264.7 细胞系中抗酒石酸酸性磷酸酶 (TRAP) 的表达，TRAP 是破骨细胞分化的遗传标志物，并抑制了细胞内 ROS 的产生。ROS 的产生激活了 NF-κB、蛋白激酶 B (AKT)、丝裂原活化蛋白激酶信号通路，如 c-JUN N 末端激酶、p38 MAP 激酶以及细胞外信号调节激酶。辛伐他汀被发现可抑制这些 H2O2 诱导的破骨细胞分化中的信号通路。总之，这些结果表明辛伐他汀通过抑制 ROS 介导的信号通路发挥破骨细胞生成抑制剂的作用。这表明辛伐他汀在骨质疏松症和病理性骨吸收方面具有潜在的用途。
