title: SOD2 and Sirt3 Control Osteoclastogenesis by Regulating Mitochondrial ROS.
abstract: 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-κB 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. © 2016 American Society for Bone and Mineral Research.
authors.affiliation: Department of Cell and Developmental Biology, BK21 Program and DRI, Seoul National University, Seoul, Korea.
authors.forename: Haemin
authors.initials: H
authors.lastname: Kim
authors.affiliation: Department of Cell and Developmental Biology, BK21 Program and DRI, Seoul National University, Seoul, Korea.
authors.forename: Yong Deok
authors.initials: YD
authors.lastname: Lee
authors.affiliation: Department of Oral Physiology, School of Dentistry, Pusan National University, Yangsan, Korea.
authors.forename: Hyung Joon
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Cell and Developmental Biology, BK21 Program and DRI, Seoul National University, Seoul, Korea.
authors.forename: Zang Hee
authors.initials: ZH
authors.lastname: Lee
authors.affiliation: Department of Cell and Developmental Biology, BK21 Program and DRI, Seoul National University, Seoul, Korea.
authors.forename: Hong-Hee
authors.initials: HH
authors.lastname: Kim
mesh_terms: D000107:Acetylation; D000818:Animals; D001862:Bone Resorption / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D005260:Female; D055785:Gene Knockdown Techniques; D008239:Lysine / Q000378:metabolism; D008813:Mice, Inbred ICR; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism*; D010012:Osteogenesis / Q000187:drug effects; D053245:RANK Ligand / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D056566:Sirtuin 3 / Q000378:metabolism*; D013482:Superoxide Dismutase / Q000378:metabolism*; D000099156:Superoxide Dismutase 2
chemical_list: D008239:Lysine; D053245:RANK Ligand; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D056566:Sirtuin 3; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2
keywords: OSTEOCLAST; RANKL; ROS; SIRT3; SOD2