Sirtuin 3 (SIRT3) maintains bone homeostasis by regulating AMPK-PGC-1? 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-?B ligand (RANKL), an essential cytokine for osteoclast differentiation. SIRT3 expression from RANKL induction depended on the transcription coactivator PGC-1? (peroxisome proliferator-activated receptor-? co-activator-1?) and the nuclear receptor ERR? (estrogen receptor-related receptor ?), and that SIRT3 inhibited the differentiation by interfering with the RANKL-induced expression of PGC-1?. Thus an auto-regulatory feedback mechanism operates to induce its own inhibitor SIRT3 by PGC-1?. 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.

SUBMITTER: Huh JE 

PROVIDER: S-EPMC4772385 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature