High-mobility group AT-Hook 1 mediates the role of nuclear factor I/X in osteogenic differentiation through activating canonical Wnt signaling
High-mobility group AT-Hook 1 mediates the role of nuclear factor I/X in osteogenic differentiation through activating canonical Wnt signaling
复制标题
高迁移率组 AT-Hook 1 通过激活经典 Wnt 信号传导介导核因子 I/X 在成骨分化中的作用
DOI：
10.1002/stem.3418
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发表时间：
2021-05-29
期刊：
影响因子：
5.2
通讯作者：
Wang, Baoli
中科院分区：
文献类型：
--
作者：
Wu, Xiaowen;Wang, Xiaochen;Wang, Baoli
此前有报道称，小鼠转录因子核因子 I/X (NFIX) 基因的缺失会损害骨的软骨内骨化和矿化。然而，该缺陷的细胞和分子基础仍未被探索。在这项研究中，我们研究了 NFIX 是否以及如何调节成骨细胞分化。 Nfix mRNA 在祖细胞的成骨和脂肪分化过程中被诱导。功能丧失和功能获得研究表明，NFIX 诱导成骨细胞分化并损害祖细胞的脂肪细胞形成。 RNA-seq 和启动子分析表明 NFIX 在转录上刺激高迁移率组 AT-Hook 1 (HMGA1) 的表达。然后我们证明 HMGA1 刺激祖细胞的成骨分化，但以成脂分化为代价。当HMGA1同时过表达时，Nfix siRNA对祖细胞分化的影响可能会减弱。进一步的研究揭示了 NFIX 和 HMGA1 对经典无翼型 MMTV 整合位点家族 (Wnt) 信号传导的刺激作用。 HMGA1 转录激活低密度脂蛋白受体相关蛋白 5 的表达。最后，将 Nfix siRNA 体内转染到小鼠骨髓中，可减少成骨细胞并增加骨髓中的脂肪积累，并使骨髓间充质干细胞中的 HMGA1/β-catenin 信号失活。这项研究表明 HMGA1 在成骨细胞定型中发挥作用，并通过转录激活经典 Wnt 信号传导介导 NFIX 的功能。
It was previously reported that the loss of the transcription factor nuclear factor I/X (NFIX) gene in mice impaired endochondral ossification and mineralization in bone. However, the cellular and molecular basis for the defect remains unexplored. In this study, we investigated if and how NFIX regulates osteoblast differentiation. Nfix mRNA was induced during osteogenic and adipogenic differentiation of progenitor cells. Loss-of-function and gain-of-function studies revealed that NFIX induced osteoblast differentiation and impaired adipocyte formation from progenitor cells. RNA-seq and promoter analysis revealed that NFIX transcriptionally stimulated the expression of high-mobility group AT-Hook 1 (HMGA1). We then demonstrated that HMGA1 stimulated osteogenic differentiation of progenitor cells at the expense of adipogenic differentiation. The effect of Nfix siRNA on the differentiation of progenitor cells could be attenuated when HMGA1 was simultaneously overexpressed. Further investigations revealed the stimulatory effect of NFIX and HMGA1 on canonical wingless-type MMTV integration site family (Wnt) signaling. HMGA1 transcriptionally activates the expression of low-density lipoprotein receptor-related protein 5. Finally, in vivo transfection of Nfix siRNA to the marrow of mice reduced osteoblasts and increased fat accumulation in the marrow, and inactivated HMGA1/beta-catenin signaling in bone marrow mesenchymal stem cells. This study suggests that HMGA1 plays a role in osteoblast commitment and mediates the function of NFIX through transcriptionally activating canonical Wnt signaling.