DLX3 promotes bone marrow mesenchymal stem cell proliferation through H19/miR-675 axis
- 13 November 2017
- journal article
- Published by Portland Press Ltd. in Clinical Science
- Vol. 131 (22), 2721-2735
- https://doi.org/10.1042/cs20171231
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.This publication has 33 references indexed in Scilit:
- The imprinted H19 gene regulates human placental trophoblast cell proliferation via encoding miR-675 that targets Nodal Modulator 1 (NOMO1)RNA Biology, 2012
- Homeodomain transcription factors regulate BMP‐2‐induced osteoactivin transcription in osteoblastsJournal of Cellular Physiology, 2011
- DLX3 Homeodomain Mutations Cause Tricho-Dento-Osseous Syndrome with Novel PhenotypesCells Tissues Organs, 2011
- The H19 locus: Role of an imprinted non‐coding RNA in growth and developmentBioEssays, 2010
- Unkämmbare Haare und atopische Dermatitis bei tricho‐dentoossärem SyndromJDDG: Journal der Deutschen Dermatologischen Gesellschaft, 2010
- H19acts as a trans regulator of the imprinted gene network controlling growth in miceDevelopment, 2009
- Dlx3 Transcriptional Regulation of Osteoblast Differentiation: Temporal Recruitment of Msx2, Dlx3, and Dlx5 Homeodomain Proteins to Chromatin of the Osteocalcin GeneMolecular and Cellular Biology, 2004
- Bone DevelopmentAnnual Review of Cell and Developmental Biology, 2000
- A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4Nature, 1993
- Tumour-suppressor activity of H19 RNANature, 1993