title: Sirtuin 3 (SIRT3) maintains bone homeostasis by regulating AMPK-PGC-1β axis in mice.
abstract: The mitochondrial sirtuin 3 (SIRT3) is involved in suppressing the onset of multiple pathologies, including cardiovascular disease, fatty liver, age-related hearing loss, and breast cancer. But a physiological role of SIRT3 in bone metabolism is not known. Here we show that SIRT3 is a key regulatory molecule to maintain bone homeostasis. Mice deficient in SIRT3 exhibited severe osteopenia owing to increased numbers of osteoclasts. Osteoclast precursors from Sirt3-/- mice underwent increased osteoclastogenesis in response to receptor activator of nuclear factor-κB ligand (RANKL), an essential cytokine for osteoclast differentiation. SIRT3 expression from RANKL induction depended on the transcription coactivator PGC-1β (peroxisome proliferator-activated receptor-γ co-activator-1β) and the nuclear receptor ERRα (estrogen receptor-related receptor α), and that SIRT3 inhibited the differentiation by interfering with the RANKL-induced expression of PGC-1β. Thus an auto-regulatory feedback mechanism operates to induce its own inhibitor SIRT3 by PGC-1β. Moreover, Sirt3-/- osteoclast precursors reduced AMP-activated protein kinase (AMPK) phosphorylation through down-regulating the expression of AMPK. Our results suggest that a mitochondrial SIRT3 is an intrinsic inhibitor for RANKL-mediated osteoclastogenesis.
authors.affiliation: Department of Life Science, Ewha Womans University, Seoul 120-750, Korea.|The Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Jeong-Eun
authors.initials: JE
authors.lastname: Huh
authors.affiliation: Department of Life Science, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Ji Hye
authors.initials: JH
authors.lastname: Shin
authors.affiliation: Department of Life Science, Ewha Womans University, Seoul 120-750, Korea.|The Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Eun Sun
authors.initials: ES
authors.lastname: Jang
authors.affiliation: Department of Life Science, Ewha Womans University, Seoul 120-750, Korea.|The Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: So Jeong
authors.initials: SJ
authors.lastname: Park
authors.affiliation: Department of Life Science, Ewha Womans University, Seoul 120-750, Korea.|The Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Doo Ri
authors.initials: DR
authors.lastname: Park
authors.affiliation: Department of Life Science, Ewha Womans University, Seoul 120-750, Korea.|The Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Ryeojin
authors.initials: R
authors.lastname: Ko
authors.affiliation: Department of Biomedical Engineering, College of Health Science, Institute of Medical Engineering, Yonsei University, Wonju 220-710, Korea.
authors.forename: Dong-Hyun
authors.initials: DH
authors.lastname: Seo
authors.affiliation: Department of Biomedical Engineering, College of Health Science, Institute of Medical Engineering, Yonsei University, Wonju 220-710, Korea.
authors.forename: Han-Sung
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Department of Oral Microbiology and Immunology, College of Dentistry, Wonkwang University, Iksan 570-749, Korea.
authors.forename: Seoung Hoon
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA 19104, USA.
authors.forename: Yongwon
authors.initials: Y
authors.lastname: Choi
authors.affiliation: The Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, Korea.|Department of Bioinspired Science, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Hyun Seok
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Department of Life Science, Ewha Womans University, Seoul 120-750, Korea.|The Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Lee
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001851:Bone Diseases, Metabolic / Q000235:genetics; D016723:Bone Remodeling / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010010:Osteoclasts / Q000166:cytology*; D010012:Osteogenesis / Q000235:genetics / Q000502:physiology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000235:genetics / Q000378:metabolism*; D053245:RANK Ligand / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D011960:Receptors, Estrogen / Q000378:metabolism*; D056566:Sirtuin 3 / Q000235:genetics / Q000378:metabolism*; D000097983:ERRalpha Estrogen-Related Receptor
chemical_list: D055372:AMP-Activated Protein Kinases; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D053245:RANK Ligand; D034741:RNA, Small Interfering; D011960:Receptors, Estrogen; D056566:Sirtuin 3; D000097983:ERRalpha Estrogen-Related Receptor; C485290:Ppargc1a protein, mouse; C525046:Sirt3 protein, mouse; C505689:Tnfsf11 protein, mouse