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Clin Sci (Lond). 2017 Nov 13;131(22):2721-2735. doi: 10.1042/CS20171231. Print 2017 Nov 15.

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

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Department of Prosthodontics, Peking University School and Hospital of Stomatology.
Department of Prosthodontics, Shanghai Stomatological Hospital.
Oral Biomedical Engineering Laboratory, Shanghai Stomatological Hospital, Fudan University.
School of Physics and Electronic Information, Henan Polytechnic University.
Stomatological Hospital of Yantai, Binzhou Medical University, Yantai.
Central Laboratory, Peking University School and Hospital of Stomatology.
Institute of Genomic Medicine, Wenzhou Medical University.
National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD.
Department of Prosthodontics, Peking University School and Hospital of Stomatology
Central Laboratory, Peking University School and Hospital of Stomatology


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.


Distal-less homeobox 3; Long noncoding RNAs H19; Tricho-dento-osseous syndrome; bone; bone marrow-derived mesenchymal stem cells; proliferation

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