Liao Xueyang, Feng Bo, Zhang Demao, Liu Peng, Zhou Xuedong, Li Ruimin, Ye Ling
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China.
Department of Endodontics, Stomatology Hospital, General Hospital of NingXia Medical University, Yinchuan, China.
PLoS One. 2017 Mar 29;12(3):e0174255. doi: 10.1371/journal.pone.0174255. eCollection 2017.
Dental Mesenchymal Cells (DMCs) are known to play a role in tooth development as well as in the repair and regeneration of dental tissue. A large number of signaling molecules regulate the proliferation and differentiation of DMC, though the underlying mechanisms are still not fully understood. Sirtuin-6 (SIRT6), a key regulator of aging, can exert an impact on embryonic stem cell (ESC) differentiation. The experimental deletion of Sirt6 in mouse bone marrow cells has been found to have an inhibiting impact on the bone mineral density and the osteogenic differentiation of these cells. The possible role of Sirt6 in tooth development, however, has at present remained largely unexplored. In the present study, we found that SIRT6 had no effect on tooth development before birth. However, Sirt6 gene deletion in knockout mice did have two post-natal impacts: a delay in tooth eruption and sluggishness in the development of dental roots. We propose an explanation of the possible molecular basis of the changes observed in Sirt6-/- mice. SIRT6 is expressed in mouse odontoblasts. Sirt6 deletion enhanced the proliferation of DMCs, as well as their capacity for adipogenic differentiation. On the other hand, it inhibited their capacity for in vitro osteogenic/chondrogenic differentiation. Further studies suggested that other factors may mediate the role of Sirt6 in odontogenesis. These include the nuclear factor kappa B (NF-κB), p38 mitogen-activated protein kinase (p38-MAPK), extracellular regulated MAP kinase (ERK) pathways and the mitochondrial energy. We demonstrated that Sirt6 plays a role in tooth root formation and confirmed that SIRT6 is necessary for DMC differentiation as well as for the development of the tooth root and for eventual tooth eruption. These results establish a new link between SIRT6 and tooth development.
牙间充质细胞（DMCs）在牙齿发育以及牙组织的修复和再生中发挥作用。大量信号分子调节DMC的增殖和分化，但其潜在机制仍未完全明确。沉默调节蛋白6（SIRT6）是衰老的关键调节因子，可对胚胎干细胞（ESC）分化产生影响。已发现实验性敲除小鼠骨髓细胞中的Sirt6对这些细胞的骨矿物质密度和成骨分化有抑制作用。然而，Sirt6在牙齿发育中的可能作用目前在很大程度上仍未得到探索。在本研究中，我们发现SIRT6在出生前对牙齿发育没有影响。然而，敲除小鼠中Sirt6基因的缺失确实有两个出生后的影响：牙齿萌出延迟和牙根发育迟缓。我们对在Sirt6-/-小鼠中观察到的变化的可能分子基础提出了解释。SIRT6在小鼠成牙本质细胞中表达。Sirt6缺失增强了DMCs的增殖及其成脂分化能力。另一方面，它抑制了它们的体外成骨/软骨分化能力。进一步的研究表明，其他因素可能介导Sirt6在牙发生中的作用。这些因素包括核因子κB（NF-κB）、p38丝裂原活化蛋白激酶（p38-MAPK）、细胞外调节MAP激酶（ERK）途径和线粒体能量。我们证明了Sirt6在牙根形成中起作用，并证实SIRT6对于DMC分化、牙根发育以及最终的牙齿萌出是必需的。这些结果建立了SIRT6与牙齿发育之间的新联系。
