Phenotypic Analysis of <i>Dlx</i>5 Overexpression in Post-natal Bone

Zhang, J.; Zhu, Jing; Valverde, Paloma; Li, L.; Pageau, Steven C.; Tu, Qisheng; Nishimura, Riko; Yoneda, Toshiyuki; Yang, Pengliang; Wen-ling, Zheng; Ma, Wei; Chen, Jake Y.

doi:10.1177/154405910808700107

Cited by 6 publications

(3 citation statements)

References 35 publications

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“…This speculation is supported by our results showing that DLX5 expression predominates in periosteal bone (Fig. 5g ), possibly due to the presence of greater numbers of osteoblasts at a specific stage of differentiation 7 , 43 , 44 . The balance between bone formation and bone resorption is essential for bone homeostasis.…”

Section: Discussionsupporting

confidence: 74%

Inhibition of STAT5A promotes osteogenesis by DLX5 regulation

et al. 2018

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The regulation of osteogenesis is important for bone formation and fracture healing. Despite advances in understanding the molecular mechanisms of osteogenesis, crucial modulators in this process are not well-characterized. Here we demonstrate that suppression of signal transducer and activator of transcription 5A (STAT5A) activates distal-less homeobox 5 (DLX5) in human bone marrow-derived stromal cells (hBMSCs) and enhances osteogenesis in vitro and in vivo. We show that STAT5A negatively regulates expression of Dlx5 in vitro and that STAT5A deletion results in increased trabecular and cortical bone mass and bone mineral density in mice. Additionally, STAT5A deletion prevents age-related bone loss. In a murine fracture model, STAT5A deletion was found to significantly enhance bone remodeling by stimulating the formation of a fracture callus. Our findings indicate that STAT5A inhibition enhances bone formation by promoting osteogenesis of BMSCs.

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Section: Discussionsupporting

confidence: 74%

Inhibition of STAT5A promotes osteogenesis by DLX5 regulation

et al. 2018

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“…Zinc deficiency caused down-regulation of dlx4a and dlx5a (Figure 4 ) while zinc supplementation has been found to induce expression of dlx2a (closest human homologue, DLX2 ) another closely related gene in the same family [ 30 ]. All members of the dlx family may be involved in formation of cartilage and/or bone and contribute to the differentiation of mineralising cell types, including osteoblasts and chondrocytes [ 46 , 47 ]. This is of interest because zinc is abundant in bone and cartilage and recent studies have demonstrated the involvement of zinc transporters in the development of such tissues [ 48 - 50 ].…”

Section: Discussionmentioning

confidence: 99%

Dynamic transcriptomic profiles of zebrafish gills in response to zinc depletion

et al. 2010

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BackgroundZinc deficiency is detrimental to organisms, highlighting its role as an essential micronutrient contributing to numerous biological processes. To investigate the underlying molecular events invoked by zinc depletion we performed a temporal analysis of transcriptome changes observed within the zebrafish gill. This tissue represents a model system for studying ion absorption across polarised epithelial cells as it provides a major pathway for fish to acquire zinc directly from water whilst sharing a conserved zinc transporting system with mammals.ResultsZebrafish were treated with either zinc-depleted (water = 2.61 μg L-1; diet = 26 mg kg-1) or zinc-adequate (water = 16.3 μg L-1; diet = 233 mg kg-1) conditions for two weeks. Gill samples were collected at five time points and transcriptome changes analysed in quintuplicate using a 16K oligonucleotide array. Of the genes represented the expression of a total of 333 transcripts showed differential regulation by zinc depletion (having a fold-change greater than 1.8 and an adjusted P-value less than 0.1, controlling for a 10% False Discovery Rate). Down-regulation was dominant at most time points and distinct sets of genes were regulated at different stages. Annotation enrichment analysis revealed that 'Developmental Process' was the most significantly overrepresented Biological Process GO term (P = 0.0006), involving 26% of all regulated genes. There was also significant bias for annotations relating to development, cell cycle, cell differentiation, gene regulation, butanoate metabolism, lysine degradation, protein tyrosin phosphatases, nucleobase, nucleoside and nucleotide metabolism, and cellular metabolic processes. Within these groupings genes associated with diabetes, bone/cartilage development, and ionocyte proliferation were especially notable. Network analysis of the temporal expression profile indicated that transcription factors foxl1, wt1, nr5a1, nr6a1, and especially, hnf4a may be key coordinators of the homeostatic response to zinc depletion.ConclusionsThe study revealed the complex regulatory pathways that allow the organism to subtly respond to the low-zinc condition. Many of the processes affected reflected a fundamental restructuring of the gill epithelium through reactivation of developmental programs leading to stem cell differentiation. The specific regulation of genes known to be involved in development of diabetes provides new molecular links between zinc deficiency and this disease. The present study demonstrates the importance of including the time-dimension in microarray studies.

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“…(2) During fracture repair, Dlx5 is strongly expressed in the regenerating blastema [Miyama et al, 1999]. (3) Five‐day‐old mice infected with retroviral vectors expressing wild‐type (WT) Dlx5 exhibit an enhanced mineralization due to an increase in the expression level of BSP and osteopontin [Zhang et al, 2008]. (4) The overexpression of Dlx5 in mesenchymal stem cells leads to reduced bone differentiation [Muraglia et al, 2008].…”

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confidence: 99%

Increased bone resorption and osteopenia in Dlx5 heterozygous mice

Samee

Geoffroy

Marty

et al. 2009

J of Cellular Biochemistry

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Distal-less (Dlx) homeobox transcription factors play a central role in the control of osteogenesis. In particular, Dlx5 regulates osteoblasts/osteoclasts coupling during perinatal bone formation. We analyze here the effect of Dlx5 allelic reduction in the control of bone remodeling. We first show that Dlx5 expression persists during postnatal bone development. We then compare the skeletal phenotype of 10- and 20-week-old Dlx5(+/-) mice to that of wild-type (WT) littermates. Dlx5(+/-) male mice exhibit lower bone mineral density (BMD) at both ages while only 20-week-old females are affected. microCT analyses reveal a reduction in cortical thickness of femoral midshafts in Dlx5(+/-) mice. Histomorphometry on distal femora shows no changes in trabecular structure and confirms a reduction in Dlx5(+/-) cortical thickness. The cortical decrease of 10-week-old mice does not derive from a reduction in periosteal bone apposition, but results from increased bone resorption with a significantly higher number of endosteal osteoclasts per bone surface and a larger marrow diameter. Urinary level of deoxypyridinoline is also higher in heterozygous mice confirming an increase in bone resorption activity. Our findings might be relevant for understanding complex, multifactorial diseases such as osteoporosis in which quantitative deregulation of gene expression leads to disruption of bone homeostasis.

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Phenotypic Analysis of Dlx5 Overexpression in Post-natal Bone

Cited by 6 publications

References 35 publications

Inhibition of STAT5A promotes osteogenesis by DLX5 regulation

Inhibition of STAT5A promotes osteogenesis by DLX5 regulation

Dynamic transcriptomic profiles of zebrafish gills in response to zinc depletion

Increased bone resorption and osteopenia in Dlx5 heterozygous mice

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