Zainabadi Kayvan, Liu Cassie J, Guarente Leonard
Glenn Center for the Science of Aging, Department of Biology, Koch Institute, MIT, Cambridge, Massachusetts, United States of America.
PLoS One. 2017 May 25;12(5):e0178520. doi: 10.1371/journal.pone.0178520. eCollection 2017.
Activation of SIRT1 has previously been shown to protect mice against osteoporosis through yet ill-defined mechanisms. In this study, we outline a role for SIRT1 as a positive regulator of the master osteoblast transcription factor, RUNX2. We find that ex vivo deletion of sirt1 leads to decreased expression of runx2 downstream targets, but not runx2 itself, along with reduced osteoblast differentiation. Reciprocally, treatment with a SIRT1 agonist promotes osteoblast differentiation, as well as the expression of runx2 downstream targets, in a SIRT1-dependent manner. Biochemical and luciferase reporter assays demonstrate that SIRT1 interacts with and promotes the transactivation potential of RUNX2. Intriguingly, mice treated with the SIRT1 agonist, resveratrol, show similar increases in the expression of RUNX2 targets in their calvaria (bone tissue), validating SIRT1 as a physiologically relevant regulator of RUNX2.
此前已有研究表明，激活SIRT1可通过尚不明确的机制保护小鼠免受骨质疏松症的影响。在本研究中，我们概述了SIRT1作为成骨细胞主转录因子RUNX2的正向调节因子的作用。我们发现，在体外敲除sirt1会导致runx2下游靶点的表达降低，但runx2本身的表达不受影响，同时成骨细胞分化也会减少。相反，用SIRT1激动剂处理可促进成骨细胞分化以及runx2下游靶点的表达，且这种促进作用依赖于SIRT1。生化和荧光素酶报告基因检测表明，SIRT1与RUNX2相互作用并促进其反式激活潜能。有趣的是，用SIRT1激动剂白藜芦醇处理的小鼠，其颅骨（骨组织）中RUNX2靶点的表达也有类似增加，这证实了SIRT1是RUNX2在生理上的相关调节因子。
