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High-Mobility Group At-Hook 1 Mediates the Role of Nuclear Factor I/X in Osteogenic Differentiation Through Activating Canonical Wnt Signaling

Wu, Xiaowen, Wang, Xiaochen, Shan, Liying, Zhou, Jie, Zhang, Xin, Zhu, Endong, Yuan, Hairui, Wang, Baoli·2021·Stem Cells
DOI 10.1002/stem.3418
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Abstract

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/β-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.

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Metadata

Authors
Wu, X., Wang, X., Shan, L., Zhou, J., Zhang, X., Zhu, E., Yuan, H., & Wang, B.
Affiliations
NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases  Chu Hsien-I Memorial Hospital and Institute of Endocrinology, Tianjin Medical University, Tianjin, People's Republic of China
ORCID
Wang, Baoli
Venue
Stem Cells
Publisher
Oxford University Press (OUP)
Published
2021-05-29
Volume
39
Issue
10
Pages
1349-1361
ISSN
  • 1066-5099
  • 1549-4918
DOI
10.1002/stem.3418
Cited by
11
References
1
Language
en
Licence
Funders
  • National Natural Science Foundation of China (81871741, 82072389, 82002263)
  • Natural Science Foundation of Tianjin City (18JCZDJC32200, 18JCQNJC12900)
  • Tianjin Medical University Chu Hsien-I Memorial Hospital and Tianjin Institute of Endocrinology (2017DX02, 2017RC01)

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