College of Stomatology, Chongqing Medical University, Chongqing, China.
Chongqing Key Laboratory for Oral Diseases and Biomedical Sciences, Chongqing, China.
Cell Prolif. 2019 Mar;52(2):e12540. doi: 10.1111/cpr.12540. Epub 2018 Nov 5.
Through loss- and gain-of-function experiments in knockout and transgenic mice, Forkhead box O (FOXO) family transcription factors have been demonstrated to play essential roles in many biological processes, including cellular proliferation, apoptosis and differentiation. Osteogenic differentiation from mesenchymal stem cells (MSCs) into osteoblasts is a well-organized process that is carefully guided and characterized by various factors, such as runt-related transcription factor 2 (Runx2), β-catenin, osteocalcin (OCN), alkaline phosphatase (ALP) and activating transcription factor 4 (ATF4). Accumulating evidence suggests multiple interactions among FOXO members and the differentiation regulatory factors listed above, resulting in an enhancement or inhibition of osteogenesis in different stages of osteogenic differentiation. To systematically and integrally understand the role of FOXOs in osteogenic differentiation and explain the contrary phenomena observed in vitro and in vivo, we herein summarized FOXO-interacting differentiation regulatory genes/factors and following alterations in differentiation. The underlying mechanism was further discussed on the basis of binding types, sites, phases and the consequent downstream transcriptional alterations of interactions among FOXOs and differentiation regulatory factors. Interestingly, a bidirectional effect of FOXOs on balancing osteogenic differentiation was discovered in MSCs. Moreover, FOXO factors are reported to be activated or suppressed by several context-dependent signalling inputs during differentiation, and the underlying molecular basis may offer new drug development targets for treatments of bone formation defect diseases.
通过敲除和转基因小鼠的功能丧失和获得实验，叉头框 O（FOXO）家族转录因子已被证明在许多生物学过程中发挥着重要作用，包括细胞增殖、凋亡和分化。间充质干细胞（MSCs）向成骨细胞的成骨分化是一个精心指导和特征明显的过程，受到各种因素的调控，如 runt 相关转录因子 2（Runx2）、β-连环蛋白、骨钙素（OCN）、碱性磷酸酶（ALP）和激活转录因子 4（ATF4）。越来越多的证据表明 FOXO 成员与上述分化调节因子之间存在多种相互作用，导致在成骨分化的不同阶段增强或抑制成骨作用。为了系统地和全面地了解 FOXOs 在成骨分化中的作用，并解释体外和体内观察到的相反现象，我们总结了 FOXO 相互作用的分化调节基因/因子以及随后在分化过程中的变化。在此基础上，进一步讨论了 FOXOs 与分化调节因子相互作用的结合类型、部位、阶段以及随后的下游转录改变的潜在机制。有趣的是，在 MSCs 中发现 FOXOs 对平衡成骨分化具有双向作用。此外，有报道称，在分化过程中，FOXO 因子会受到几种依赖于背景的信号输入的激活或抑制，其潜在的分子基础可能为骨形成缺陷疾病的治疗提供新的药物开发靶点。
