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: Jeong-Eun Huh, Ji Hye Shin, Eun Sun Jang, So Jeong Park, Doo Ri Park, Ryeojin Ko, Dong-Hyun Seo, Han-Sung Kim, Seoung Hoon Lee, Yongwon Choi, Hyun Seok Kim, Soo Young Lee
• Journal: Scientific reports (Sci Rep) Vol. 6 Pg. 22511 (Mar 01 2016) ISSN: 2045-2322 [Electronic] England
• PMID: 26928655 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
• Ppargc1a protein, mouse
• RANK Ligand
• RNA, Small Interfering
• Receptors, Estrogen
• Sirt3 protein, mouse
• Tnfsf11 protein, mouse
• AMP-Activated Protein Kinases
• Sirtuin 3

Topics

• AMP-Activated Protein Kinases (metabolism)
• Animals
• Bone Diseases, Metabolic (genetics)
• Bone Remodeling (genetics, physiology)
• Cells, Cultured
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Osteoclasts (cytology)
• Osteogenesis (genetics, physiology)
• Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha (genetics, metabolism)
• RANK Ligand (metabolism)
• RNA Interference
• RNA, Small Interfering (genetics)
• Receptors, Estrogen (metabolism)
• Sirtuin 3 (genetics, metabolism)
• ERRalpha Estrogen-Related Receptor