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DLX3 promotes bone marrow mesenchymal stem cell proliferation through H19/miR-675 axis.

Authors
  • Zhao, Na1, 2, 3
  • Zeng, Li1
  • Liu, Yang1
  • Han, Dong1
  • Liu, Haochen1
  • Xu, Jian4
  • Jiang, Yuxi5
  • Li, Cuiying6
  • Cai, Tao7, 8
  • Feng, Hailan9
  • Wang, Yixiang10
  • 1 Department of Prosthodontics, Peking University School and Hospital of Stomatology.
  • 2 Department of Prosthodontics, Shanghai Stomatological Hospital.
  • 3 Oral Biomedical Engineering Laboratory, Shanghai Stomatological Hospital, Fudan University.
  • 4 School of Physics and Electronic Information, Henan Polytechnic University.
  • 5 Stomatological Hospital of Yantai, Binzhou Medical University, Yantai.
  • 6 Central Laboratory, Peking University School and Hospital of Stomatology.
  • 7 Institute of Genomic Medicine, Wenzhou Medical University.
  • 8 National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD.
  • 9 Department of Prosthodontics, Peking University School and Hospital of Stomatology [email protected] [email protected]
  • 10 Central Laboratory, Peking University School and Hospital of Stomatology [email protected] [email protected]
Type
Published Article
Journal
Clinical Science
Publisher
Portland Press
Publication Date
Nov 15, 2017
Volume
131
Issue
22
Pages
2721–2735
Identifiers
DOI: 10.1042/CS20171231
PMID: 28963438
Source
Medline
Keywords
License
Unknown

Abstract

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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