N-myc downstream regulated gene 1 suppresses osteoblast differentiation through inactivating Wnt/β-catenin signaling.
N-myc downstream regulated gene 1 suppresses osteoblast differentiation through inactivating Wnt/β-catenin signaling.
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N-myc 下游调节基因 1 通过失活 Wnt/β-catenin 信号抑制成骨细胞分化
DOI：
10.1186/s13287-022-02714-5
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发表时间：
2022-02-04
影响因子：
7.5
通讯作者：
Wang B
中科院分区：
文献类型：
--
作者：
Shi X;Cen Y;Shan L;Tian L;Zhu E;Yuan H;Li X;Liu Y;Wang B
背景N-myc下游调节基因1（NDRG 1）在包括破骨细胞分化在内的多种生物学过程中发挥作用。然而，目前还不知道NDRG 1是否以及如何调节骨髓基质祖细胞的成骨分化。MethodsGene expression profiling analysis进行研究NDRG 1在成骨和成脂分化过程中的表达水平。通过功能获得和/或功能丧失实验研究NDRG 1在骨髓基质祖细胞增殖和分化中的作用，并探讨其作用机制。最后，在体内转染NDRG 1 siRNA做和其对成骨和成脂分化在小鼠explored.ResultsGene表达谱分析显示，NDRG 1水平调节成骨和成脂分化的祖细胞。功能实验表明，NDRG 1负调控细胞生长，并且NDRG 1调节骨髓基质祖细胞的成骨和成脂定向，以成骨细胞分化为代价驱动细胞向脂肪细胞分化。此外，NDRG 1与基质祖细胞中的低密度脂蛋白受体相关蛋白6（LRP 6）相互作用，并灭活经典的Wnt/β-catenin信号级联反应。此外，β-catenin的沉默可减轻Ndrg 1 siRNA诱导的祖细胞分化障碍。最后，将Ndrg 1 siRNA体内转染到小鼠骨髓中防止了卵巢切除小鼠BMSC中经典Wnt信号转导的失活，结论NDRG 1基因在骨髓基质祖细胞成骨成脂定向分化中起重要作用，NDRG 1基因的表达可促进骨髓基质祖细胞成骨成脂定向分化细胞通过灭活经典Wnt信号传导。
BackgroundN-myc downstream regulated gene 1 (NDRG1) plays a role in a variety of biological processes including differentiation of osteoclasts. However, it is not known if and how NDRG1 regulates osteogenic differentiation of marrow stromal progenitor cells.MethodsGene expression profiling analysis was performed to study the expression level of Ndrg1 during osteogenic and adipogenic differentiation. Gain-of-function and/or loss-of function experiments were carried out to study the role of NDRG1 in the proliferation and differentiation of marrow stromal progenitor cells and the mechanism underlying the function was investigated. Finally, in vivo transfection of Ndrg1 siRNA was done and its effect on osteogenic and adipogenic differentiation in mice was explored.ResultsGene expression profiling analysis revealed that NDRG1 level was regulated during osteogenic and adipogenic differentiation of progenitor cells. The functional experiments demonstrated that NDRG1 negatively regulated the cell growth, and reciprocally modulated the osteogenic and adipogenic commitment of marrow stromal progenitor cells, driving the cells to differentiate toward adipocytes at the expense of osteoblast differentiation. Moreover, NDRG1 interacted with low-density lipoprotein receptor-related protein 6 (LRP6) in the stromal progenitor cells and inactivated the canonical Wnt/β-catenin signaling cascade. Furthermore, the impaired differentiation of progenitor cells induced by Ndrg1 siRNA could be attenuated when β-catenin was simultaneously silenced. Finally, in vivo transfection of Ndrg1 siRNA to the marrow of mice prevented the inactivation of canonical Wnt signaling in the BMSCs of ovariectomized mice, and ameliorated the reduction of osteoblasts on the trabeculae and increase of fat accumulation in the marrow observed in the ovariectomized mice.ConclusionThis study has provided evidences that NDRG1 plays a role in reciprocally modulating osteogenic and adipogenic commitment of marrow stromal progenitor cells through inactivating canonical Wnt signaling.