| First Author | Huh JE | Year | 2016 |
| Journal | Sci Rep | Volume | 6 |
| Pages | 22511 | PubMed ID | 26928655 |
| Mgi Jnum | J:287494 | Mgi Id | MGI:6407603 |
| Doi | 10.1038/srep22511 | Citation | Huh JE, et al. (2016) Sirtuin 3 (SIRT3) maintains bone homeostasis by regulating AMPK-PGC-1beta axis in mice. Sci Rep 6:22511 |
| abstractText | 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-kappaB ligand (RANKL), an essential cytokine for osteoclast differentiation. SIRT3 expression from RANKL induction depended on the transcription coactivator PGC-1beta (peroxisome proliferator-activated receptor-gamma co-activator-1beta) and the nuclear receptor ERRalpha (estrogen receptor-related receptor alpha), and that SIRT3 inhibited the differentiation by interfering with the RANKL-induced expression of PGC-1beta. Thus an auto-regulatory feedback mechanism operates to induce its own inhibitor SIRT3 by PGC-1beta. 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. |
