Dlx genes and the maintenance of bone homeostasis and skeletal integrity

Levi, Giovanni; Gitton, Yorick

doi:10.1038/cdd.2014.94

Cited by 10 publications

(8 citation statements)

References 21 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Given the fact that the bone homeostasis is an intricate process orchestrated by hundreds of factors, an interesting concept that emerges is that DLX3 performs its role in osteogenesis by coordinating with other osteogenic differentiation essential factors and constituting a regulatory network to keep the maintenance of bone homeostasis36. Firstly, DLX3 gene belongs to a Dlx homeobox transcription factors family, which consists of three inverted and convergent clusters ( Dlx1/2, Dlx3/4 and Dlx5/6 ), and have essential function in skeleton development23738.…”

Section: Discussionmentioning

confidence: 99%

Senescence: novel insight into DLX3 mutations leading to enhanced bone formation in Tricho-Dento-Osseous syndrome

Zhao

Han

Liu

et al. 2016

Sci Rep

View full text Add to dashboard Cite

The homeodomain transcription factor distal-less homeobox 3 gene (DLX3) is required for hair, tooth and skeletal development. DLX3 mutations have been found to be responsible for Tricho-Dento-Osseous (TDO) syndrome, characterized by kinky hair, thin-pitted enamel and increased bone density. Here we show that the DLX3 mutation (c.533 A>G; Q178R) attenuates osteogenic potential and senescence of bone mesenchymal stem cells (BMSCs) isolated from a TDO patient, providing a molecular explanation for abnormal increased bone density. Both DLX3 mutations (c.533 A>G and c.571_574delGGGG) delayed cellular senescence when they were introduced into pre-osteoblastic cells MC3T3-E1. Furthermore, the attenuated skeletal aging and bone loss in DLX3 (Q178R) transgenic mice not only reconfirmed that DLX3 mutation (Q178R) delayed cellular senescence, but also prevented aging-mediated bone loss. Taken together, these results indicate that DLX3 mutations act as a loss of function in senescence. The delayed senescence of BMSCs leads to increased bone formation by compensating decreased osteogenic potentials with more generations and extended functional lifespan. Our findings in the rare human genetic disease unravel a novel mechanism of DLX3 involving the senescence regulation of bone formation.

show abstract

Section: Discussionmentioning

confidence: 99%

Senescence: novel insight into DLX3 mutations leading to enhanced bone formation in Tricho-Dento-Osseous syndrome

Zhao

Han

Liu

et al. 2016

Sci Rep

View full text Add to dashboard Cite

show abstract

“…FGF18 stimulates rat and mouse MSCs for their osteogenic differentiation (Charoenlarp et al, 2017;Jing et al, 2018). DLX3 serves as a negative regulator of osteogenesis and contributes to bone homeostasis with other transcription factors, such as DLX5 (Levi and Gitton, 2014). Also, Cyp26b1 has effect in osteoblast and Cxcl5 functions for mobilizing HSC away from BM.…”

Section: Discussionmentioning

confidence: 99%

“…We observed that 24 genes were upregulated in Dnmt3l KO MSCs and hypermethylated at the gene bodies in Dnmt3l KD ES cells ( Figure 4I and more comprehensive analysis summarized in Supplementary Figure 6), with a very low p-value < 1.387e-04, indicating the significant overlap based on the hypergeometric distribution test. Of the 24 genes, some gene products have been reported to tie with skeletal development or homeostasis, with a few of them acting directly in MSCs to regulate osteogenic differentiation, namely, HIEVP3 and GATA2 inhibiting BMPinduced osteogenesis (Tolkachov et al, 2018;Li et al, 2020), DLX3 being a negative modulator (Levi and Gitton, 2014), while FGF18 and Wnt10a providing stimulatory signal (Charoenlarp et al, 2017;Jing et al, 2018). Those results suggest that the occurrence of DNMT3L-mediated epigenetic legacy, if any, may be observed in limited genes in cultured MSCs.…”

Section: Searching For Potential Dnmt3l-mediated Epigenetic Memory Frmentioning

confidence: 93%

Transcriptome Analysis of Dnmt3l Knock-Out Mice Derived Multipotent Mesenchymal Stem/Stromal Cells During Osteogenic Differentiation

Yang

Lee

et al. 2021

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Multipotent mesenchymal stem/stromal cells (MSCs) exhibit great potential for cell-based therapy. Proper epigenomic signatures in MSCs are important for the maintenance and the subsequent differentiation potential. The DNA methyltransferase 3-like (DNMT3L) that was mainly expressed in the embryonic stem (ES) cells and the developing germ cells plays an important role in shaping the epigenetic landscape. Here, we report the reduced colony forming ability and impaired in vitro osteogenesis in Dnmt3l-knockout-mice-derived MSCs (Dnmt3l KO MSCs). By comparing the transcriptome between undifferentiated Dnmt3l KO MSCs and the MSCs from the wild-type littermates, some of the differentially regulated genes (DEGs) were found to be associated with bone-morphology-related phenotypes. On the third day of osteogenic induction, differentiating Dnmt3l KO MSCs were enriched for genes associated with nucleosome structure, peptide binding and extracellular matrix modulation. Differentially expressed transposable elements in many subfamilies reflected the change of corresponding regional epigenomic signatures. Interestingly, DNMT3L protein is not expressed in cultured MSCs. Therefore, the observed defects in Dnmt3l KO MSCs are unlikely a direct effect from missing DNMT3L in this cell type; instead, we hypothesized them as an outcome of the pre-deposited epigenetic signatures from the DNMT3L-expressing progenitors. We observed that 24 out of the 107 upregulated DEGs in Dnmt3l KO MSCs were hypermethylated in their gene bodies of DNMT3L knock-down ES cells. Among these 24 genes, some were associated with skeletal development or homeostasis. However, we did not observe reduced bone development, or reduced bone density through aging in vivo. The stronger phenotype in vitro suggested the involvement of potential spreading and amplification of the pre-deposited epigenetic defects over passages, and the contribution of oxidative stress during in vitro culture. We demonstrated that transient deficiency of epigenetic co-factor in ES cells or progenitor cells caused compromised property in differentiating cells much later. In order to facilitate safer practice in cell-based therapy, we suggest more in-depth examination shall be implemented for cells before transplantation, even on the epigenetic level, to avoid long-term risk afterward.

show abstract

“…Starting at mid gestation, Dlx2, Dlx3, Dlx5 , and Dlx6 are expressed in most sites of cartilage condensation and in differentiating osteoblasts in areas of bone formation [ 36 , 60 , 61 , 62 ]. As will be detailed later, the expression of Dlx genes persists then throughout life both in precursor bone marrow mesenchymal stem cells (BM-MSCs) and in differentiated chondrocytes and osteoblasts, suggesting their involvement in bone remodeling.…”

Section: DLX Genes In Skeletal Morphogenesis Differentiation...mentioning

confidence: 99%

DLX Genes in the Development and Maintenance of the Vertebrate Skeleton: Implications for Human Pathologies

Levi

Narboux-Nême

Cohen‐Solal

2022

Cells

View full text Add to dashboard Cite

Skeletal shape and mechanical properties define, to a large extent, vertebrate morphology and physical capacities. During development, skeletal morphogenesis results from dynamic communications between chondrocytes, osteoblasts, osteoclasts, and other cellular components of the skeleton. Later in life, skeletal integrity depends on the regulatory cascades that assure the equilibrium between bone formation and resorption. Finally, during aging, skeletal catabolism prevails over anabolism resulting in progressive skeletal degradation. These cellular processes depend on the transcriptional cascades that control cell division and differentiation in each cell type. Most Distal-less (Dlx) homeobox transcription factors are directly involved in determining the proliferation and differentiation of chondrocytes and osteoblasts and, indirectly, of osteoclasts. While the involvement of Dlx genes in the regulation of skeletal formation has been well-analyzed thanks to several mutant mouse models, the role of these genes in the maintenance of bone integrity has been only partially studied. The importance of Dlx genes for adult bone tissues is evidenced by their central role in the regulatory pathways involving Osx/Sp7 and Runx2, the two major master genes of osteogenesis. Dlx genes appear to be involved in several bone pathologies including, for example, osteoporosis. Indeed, at least five large-scale GWAS studies which aimed to detect loci associated with human bone mineral density (BMD) have identified a known DLX5/6 regulatory region within chromosome 7q21.3 in proximity of SEM1/FLJ42280/DSS1 coding sequences, suggesting that DLX5/6 expression is critical in determining healthy BMD. This review aims to summarize the major findings concerning the involvement of Dlx genes in skeletal development and homeostasis and their involvement in skeletal aging and pathology.

show abstract

Dlx genes and the maintenance of bone homeostasis and skeletal integrity

Cited by 10 publications

References 21 publications

Senescence: novel insight into DLX3 mutations leading to enhanced bone formation in Tricho-Dento-Osseous syndrome

Senescence: novel insight into DLX3 mutations leading to enhanced bone formation in Tricho-Dento-Osseous syndrome

Transcriptome Analysis of Dnmt3l Knock-Out Mice Derived Multipotent Mesenchymal Stem/Stromal Cells During Osteogenic Differentiation

DLX Genes in the Development and Maintenance of the Vertebrate Skeleton: Implications for Human Pathologies

Contact Info

Product

Resources

About