SOD2 and Sirt3 Control Osteoclastogenesis by Regulating Mitochondrial ROS
SOD2 and Sirt3 Control Osteoclastogenesis by Regulating Mitochondrial ROS
复制标题
DOI：
10.1002/jbmr.2974
复制
发表时间：
2017-02-01
影响因子：
6.2
通讯作者：
Kim, Hong-Hee
中科院分区：
文献类型：
--
作者：
Kim, Haemin;Lee, Yong Deok;Kim, Hong-Hee
活性氧（ROS）是各种细胞类型（包括骨细胞）中细胞信号转导不可或缺的元素。特别是，破骨细胞（OC），专门用于骨吸收的细胞，利用ROS作为第二信使在NF-κ配体（RANKL）的受体活化剂（B配体）诱导的分化和活化。此外，由于骨吸收活性的高能量需求，OC含有大量的线粒体，这是大部分总ROS的来源。在这项研究中，我们专注于从线粒体产生的ROS在破骨细胞的调控。我们观察到RANKL可增加线粒体超氧化物歧化酶2（SOD 2）（一种负责减少线粒体中超氧化物自由基的酶）的水平。siRNA介导的SOD 2敲低（KD）增加了ROS水平并增强了OC分化。相反，过表达SOD 2通过降低ROS水平减少破骨细胞生成。此外，我们发现NAD依赖性脱乙酰酶sirtuin 3（Sirt 3），线粒体中的SOD 2的激活剂，被RANKL诱导。靶向Sirt 3的siRNA通过减少SOD 2的赖氨酸68的脱乙酰化而降低SOD 2活性，导致破骨细胞生成增加。此外，在ICR小鼠颅骨中SOD 2或Sirt 3的体内KD降低了骨体积并增加了OC表面，支持体外实验的结果。综上所述，我们的研究结果首次证明了SOD 2和Sirt 3对线粒体ROS的调节在OC分化程序的微调中起着重要作用。(C)2016年美国骨与矿物质研究学会。
Reactive oxygen species (ROS) are an indispensable element of cellular signal transduction in various cell types, including bone cells. In particular, osteoclasts (OCs), cells specialized for bone resorption, utilize ROS as second messengers during receptor activator of NF-kappa B ligand (RANKL)-induced differentiation and activation. In addition, because of the high energy demands of bone-resorbing activity, OCs contain large amounts of mitochondria, the source of the majority of total ROS. In this study, we focused on the regulation of ROS generated from mitochondria during osteoclastogenesis. We observed that the level of mitochondrial superoxide dismutase 2 (SOD2), an enzyme responsible for reducing superoxide radicals in mitochondria, was increased by RANKL. siRNA-mediated knockdown (KD) of SOD2 increased ROS levels and enhanced OC differentiation. Conversely, overexpression of SOD2 reduced osteoclastogenesis by decreasing ROS levels. Moreover, we found that NAD-dependent deacetylase sirtuin 3 (Sirt3), an activator of SOD2 in mitochondria, was induced by RANKL. Sirt3-targeted siRNA decreased SOD2 activity by reducing deacetylation of lysine 68 of SOD2, leading to increased osteoclastogenesis. Furthermore, in vivo KD of SOD2 or Sirt3 in ICR mouse calvariae decreased bone volume and increased OC surface, supporting the results of in vitro experiments. Taken together, our findings demonstrate for the first time to our knowledge that the regulation of mitochondrial ROS by SOD2 and Sirt3 plays an important role in fine-tuning the OC differentiation program. (C) 2016 American Society for Bone and Mineral Research.