Department of Life Science, Ewha Womans University, Seoul 120-750, Korea.
The Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, Korea.
Sci Rep. 2016 Mar 1;6:22511. doi: 10.1038/srep22511.
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.
线粒体中的沉默调节蛋白 3（SIRT3）参与抑制多种病理学的发生，包括心血管疾病、脂肪肝、与年龄相关的听力损失和乳腺癌。但是，SIRT3 在骨代谢中的生理作用尚不清楚。在这里，我们表明 SIRT3 是维持骨稳态的关键调节分子。缺乏 SIRT3 的小鼠由于破骨细胞数量增加而表现出严重的骨质疏松症。来自 Sirt3-/- 小鼠的破骨细胞前体对核因子-κB 配体（RANKL）的反应性增强，RANKL 是破骨细胞分化的必需细胞因子。SIRT3 的表达依赖于转录共激活因子 PGC-1β（过氧化物酶体增殖物激活受体-γ 共激活因子-1β）和核受体 ERRα（雌激素受体相关受体 α），并且 SIRT3 通过干扰 RANKL 诱导的 PGC-1β 的表达来抑制分化。因此，通过 PGC-1β 诱导自身抑制剂 SIRT3 的自动反馈调节机制发挥作用。此外，Sirt3-/-破骨细胞前体通过下调 AMPK 的表达来减少 AMP 激活的蛋白激酶（AMPK）磷酸化。我们的结果表明，线粒体 SIRT3 是 RANKL 介导的破骨细胞发生的内在抑制剂。
