The underlying molecular mechanism of the increased bone mass phenotype in Tricho-dento-osseous (TDO) syndrome remains largely unknown. Our previous study has shown that the TDO point mutation c.533A>G, Q178R in DLX3 could increase bone density in a TDO patient and transgenic mice partially through delaying senescence in bone marrow mesenchymal stem cells (BMSCs). In the present study, we provided a new complementary explanation for TDO syndrome: the DLX3 (Q178R) mutation increased BMSCs proliferation through H19/miR-675 axis. We found that BMSCs derived from the TDO patient (TDO-BMSCs) had stronger proliferation ability than controls by clonogenic and CCK-8 assays. Next, experiments of overexpression and knockdown of wild-type DLX3 via lentiviruses in normal BMSCs confirmed the results by showing its negative role in cell proliferation. Through validated high-throughput data, we found that the DLX3 mutation reduced the expression of H19 and its coexpression product miR-675 in BMSCs. Function and rescue assays suggested that DLX3, long noncoding RNA H19, and miR-675 are negative factors in modulation of BMSCs proliferation as well as NOMO1 expression. The original higher proliferation rate and the expression of NOMO1 in TDO-BMSCs were suppressed after H19 restoration. Collectively, it indicates that DLX3 regulates BMSCs proliferation through H19/miR-675 axis. Moreover, the increased expression of NOMO1 and decreased H19/miR-675 expression in DLX3 (Q178R) transgenic mice, accompanying with accrual bone mass and density detected by micro-CT, further confirmed our hypothesis. In summary, we, for the first time, demonstrate that DLX3 mutation interferes with bone formation partially through H19/miR-675/NOMO1 axis in TDO syndrome.
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An atherosclerotic plaque. In Clinical Science volume 131, issue 21, Martín-Núñez et al. report on the relationship between Klotho, an anti-aging factor expressed in arterial walls, and inflammation in human atherosclerotic disease. For details, see pages 2601–2609.
Research Article|
November 13 2017
DLX3 promotes bone marrow mesenchymal stem cell proliferation through H19/miR-675 axis
Na Zhao;
Na Zhao
1Department of Prosthodontics, Peking University School and Hospital of Stomatology
2Department of Prosthodontics, Shanghai Stomatological Hospital
3Oral Biomedical Engineering Laboratory, Shanghai Stomatological Hospital, Fudan University
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Li Zeng;
Li Zeng
1Department of Prosthodontics, Peking University School and Hospital of Stomatology
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Yang Liu;
Yang Liu
1Department of Prosthodontics, Peking University School and Hospital of Stomatology
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Dong Han;
Dong Han
1Department of Prosthodontics, Peking University School and Hospital of Stomatology
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Haochen Liu;
Haochen Liu
1Department of Prosthodontics, Peking University School and Hospital of Stomatology
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Jian Xu;
Jian Xu
4School of Physics and Electronic Information, Henan Polytechnic University
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Yuxi Jiang;
Yuxi Jiang
5Stomatological Hospital of Yantai, Binzhou Medical University, Yantai
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Cuiying Li;
Cuiying Li
6Central Laboratory, Peking University School and Hospital of Stomatology
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Tao Cai;
Tao Cai
7Institute of Genomic Medicine, Wenzhou Medical University
8National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD
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Hailan Feng;
1Department of Prosthodontics, Peking University School and Hospital of Stomatology
Correspondence: Hailan Feng ([email protected]) and Yixiang Wang ([email protected])
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Yixiang Wang
6Central Laboratory, Peking University School and Hospital of Stomatology
Correspondence: Hailan Feng ([email protected]) and Yixiang Wang ([email protected])
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Publisher: Portland Press Ltd
Received:
July 17 2017
Revision Received:
September 03 2017
Accepted:
September 27 2017
Accepted Manuscript online:
September 28 2017
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2017 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2017
Clin Sci (Lond) (2017) 131 (22): 2721–2735.
Article history
Received:
July 17 2017
Revision Received:
September 03 2017
Accepted:
September 27 2017
Accepted Manuscript online:
September 28 2017
Citation
Na Zhao, Li Zeng, Yang Liu, Dong Han, Haochen Liu, Jian Xu, Yuxi Jiang, Cuiying Li, Tao Cai, Hailan Feng, Yixiang Wang; DLX3 promotes bone marrow mesenchymal stem cell proliferation through H19/miR-675 axis. Clin Sci (Lond) 15 November 2017; 131 (22): 2721–2735. doi: https://doi.org/10.1042/CS20171231
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