PMID- 27540894 OWN - NLM STAT- MEDLINE DCOM- 20180108 LR - 20180108 IS - 1523-4681 (Electronic) IS - 0884-0431 (Linking) VI - 32 IP - 2 DP - 2017 Feb TI - SOD2 and Sirt3 Control Osteoclastogenesis by Regulating Mitochondrial ROS. PG - 397-406 LID - 10.1002/jbmr.2974 [doi] AB - 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-kappaB 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. CI - (c) 2016 American Society for Bone and Mineral Research. FAU - Kim, Haemin AU - Kim H AD - Department of Cell and Developmental Biology, BK21 Program and DRI, Seoul National University, Seoul, Korea. FAU - Lee, Yong Deok AU - Lee YD AD - Department of Cell and Developmental Biology, BK21 Program and DRI, Seoul National University, Seoul, Korea. FAU - Kim, Hyung Joon AU - Kim HJ AD - Department of Oral Physiology, School of Dentistry, Pusan National University, Yangsan, Korea. FAU - Lee, Zang Hee AU - Lee ZH AD - Department of Cell and Developmental Biology, BK21 Program and DRI, Seoul National University, Seoul, Korea. FAU - Kim, Hong-Hee AU - Kim HH AD - Department of Cell and Developmental Biology, BK21 Program and DRI, Seoul National University, Seoul, Korea. LA - eng PT - Journal Article DEP - 20160907 PL - England TA - J Bone Miner Res JT - Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research JID - 8610640 RN - 0 (RANK Ligand) RN - 0 (RNA, Small Interfering) RN - 0 (Reactive Oxygen Species) RN - EC 1.15.1.1 (Superoxide Dismutase) RN - EC 1.15.1.1 (superoxide dismutase 2) RN - EC 3.5.1.- (Sirtuin 3) RN - K3Z4F929H6 (Lysine) SB - IM MH - Acetylation MH - Animals MH - Bone Resorption/pathology MH - Cell Differentiation/drug effects MH - Female MH - Gene Knockdown Techniques MH - Lysine/metabolism MH - Mice, Inbred ICR MH - Mitochondria/drug effects/metabolism MH - Osteoclasts/drug effects/*metabolism MH - *Osteogenesis/drug effects MH - RANK Ligand/pharmacology MH - RNA, Small Interfering/metabolism MH - Reactive Oxygen Species/*metabolism MH - Sirtuin 3/*metabolism MH - Superoxide Dismutase/*metabolism OTO - NOTNLM OT - OSTEOCLAST OT - RANKL OT - ROS OT - SIRT3 OT - SOD2 EDAT- 2016/08/20 06:00 MHDA- 2018/01/09 06:00 CRDT- 2016/08/20 06:00 PHST- 2016/04/13 00:00 [received] PHST- 2016/08/08 00:00 [revised] PHST- 2016/08/16 00:00 [accepted] PHST- 2016/08/20 06:00 [pubmed] PHST- 2018/01/09 06:00 [medline] PHST- 2016/08/20 06:00 [entrez] AID - 10.1002/jbmr.2974 [doi] PST - ppublish SO - J Bone Miner Res. 2017 Feb;32(2):397-406. doi: 10.1002/jbmr.2974. Epub 2016 Sep 7.