Runx2 Protein Represses Axin2 Expression in Osteoblasts and Is Required for Craniosynostosis in Axin2-deficient Mice*

McGee‐Lawrence, Meghan E.; Li, Xiaodong; Bledsoe, Krista L.; Wu, Hai; Hawse, John R.; Subramaniam, Malayannan; Razidlo, David F.; Stensgard, Bridget; Stein, Gary S.; Wijnen, André J. van; Lian, Jane B.; Hsu, Wei-Hsuan

doi:10.1074/jbc.m112.414995

Cited by 32 publications

(35 citation statements)

References 54 publications

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“…Since expression of osteoblast differentiation marker genes and osteoblast mineralization were regulated by miR-15b (Fig. 2), and Runx2 activity can be altered by the post translational mechanisms such as acetylation, ubiquitination, phosphorylation, protein-protein interactions (Jeon et al, 2006; Wang et al, 2013; Boumah et al, 2009; McGee-Lawrence et al, 2013; Lengner et al, 2005), we determined Runx2 protein expression. Human MSCs were transiently transfected with either negative control or miR-15b inhibitor and were allowed to differentiate them.…”

Section: Resultsmentioning

confidence: 99%

A Positive Role of MicroRNA‐15b on Regulation of Osteoblast Differentiation

Vimalraj

Partridge

Selvamurugan

2014

Journal Cellular Physiology

146

115

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Osteoblast differentiation is tightly regulated by several factors including microRNAs (miRNAs). In this paper we report that pre-mir-15b is highly expressed in differentiated osteoblasts. The functional role of miR-15b in osteoblast differentiation was determined using miR-15b mimic/inhibitor and the expression of osteoblast differentiation marker genes such as alkaline phosphatase (ALP), type I collagen genes was decreased by miR-15b inhibitor. Runx2, a bone specific transcription factor is generally required for expression of osteoblast differentiation marker genes and in response to miR-15b inhibitor treatment, Runx2 mRNA expression was not changed; whereas its protein expression was decreased. Even though Smurf1 (SMAD specific E3 ubiquitin protein ligase 1), HDAC4 (histone deacetylase 4), Smad7, and Crim1 were found to be few of miR-15b’s putative target genes, there was increased expression of only Smurf1 gene at mRNA and protein levels by miR-15b inhibitor. miR-15b mimic treatment significantly increased and decreased expressions of Runx2 and Smurf1 proteins, respectively. We further identified that the Smurf1 3’UTR is directly targeted by miR-15b using the luciferase reporter gene system. This is well documented that Smurf1 interacts with Runx2 and degrades it by proteasomal pathway. Hence, based on our results we suggest that miR-15b promotes osteoblast differentiation by indirectly protecting Runx2 protein from Smurf1 mediated degradation. Thus, this study identified that miR-15b can act as a positive regulator for osteoblast differentiation.

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Section: Resultsmentioning

confidence: 99%

A Positive Role of MicroRNA‐15b on Regulation of Osteoblast Differentiation

Vimalraj

Partridge

Selvamurugan

2014

Journal Cellular Physiology

146

115

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“…Other gene that is essential to induce osteogenesis is the RUNX-2 [32,33]. RUNX2 is a member of the RUNX family, and it is important for osteoblastic differentiation and skeletal morphogenesis and acts on regulatory factors involved in skeletal gene expression [34]. In this way, BMP and Runx2 serve as upstream and downstream Banchors^in the pathway that drives osteoblast differentiation [35].…”

Section: Discussionmentioning

confidence: 99%

Effects of low-level laser therapy on the expression of osteogenic genes during the initial stages of bone healing in rats: a microarray analysis

et al. 2015

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This study evaluated the morphological changes produced by LLLT on the initial stages of bone healing and also studied the pathways that stimulate the expression of genes related to bone cell proliferation and differentiation. One hundred Wistar rats were divided into control and treated groups. Noncritical size bone defects were surgically created at the upper third of the tibia. Laser irradiation (Ga-Al-As laser 830 nm, 30 mW, 94 s, 2.8 J) was performed for 1, 2, 3, 5, and 7 sessions. Histopathology revealed that treated animals produced increased amount of newly formed bone at the site of the injury. Moreover, microarray analysis evidenced that LLLT produced a significant increase in the expression TGF-β, BMP, FGF, and RUNX-2 that could stimulate osteoblast proliferation and differentiation, which may be related to improving the deposition of newly formed bone at the site of the injury. Thus, it is possible to conclude that LLLT improves bone healing by producing a significant increase in the expression of osteogenic genes.

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“…Axin2 is a scaffold protein that suppresses canonical Wnt signaling by facilitating the degradation of ␤-catenin (29). We recently showed that HDAC3 suppresses Axin2 transcription and that Axin2 is regulated by Runx2 in osteoblasts (28). Basal acetylated H4 was detected on the Axin2 promoter in control cells treated with vehicle, but it was Ͼ10-fold higher in SAHA treated cells (Fig.…”

Section: Saha Enhances Osteoblast Differentiation and Induces Histonementioning

confidence: 99%

“…We assessed the acetylation status of acetylated H4 on this DNA region in the presence of SAHA or vehicle (DMSO) (28). Axin2 is a scaffold protein that suppresses canonical Wnt signaling by facilitating the degradation of ␤-catenin (29).…”

Section: Saha Enhances Osteoblast Differentiation and Induces Histonementioning

confidence: 99%

Histone Deacetylase Inhibition Promotes Osteoblast Maturation by Altering the Histone H4 Epigenome and Reduces Akt Phosphorylation

Dudakovic¹,

Evans²,

Li³

et al. 2013

Journal of Biological Chemistry

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Background: Histone deacetylase (HDAC) inhibition promotes bone formation in vitro via undefined epigenetic events. Results: Microarray and ChIP-Seq analyses revealed genomic areas where H4 acetylation is altered by HDAC inhibitors and identified differentially regulated genes. Conclusion: Suberoylanilide hydroxamic acid increases H4 acetylation and suppresses phosphorylation of insulin/Akt signaling mediators in osteoblasts. Significance: Epigenetic profiling is a powerful means to gain mechanistic insights into bone anabolic processes.

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Runx2 Protein Represses Axin2 Expression in Osteoblasts and Is Required for Craniosynostosis in Axin2-deficient Mice*

Cited by 32 publications

References 54 publications

A Positive Role of MicroRNA‐15b on Regulation of Osteoblast Differentiation

A Positive Role of MicroRNA‐15b on Regulation of Osteoblast Differentiation

Effects of low-level laser therapy on the expression of osteogenic genes during the initial stages of bone healing in rats: a microarray analysis

Histone Deacetylase Inhibition Promotes Osteoblast Maturation by Altering the Histone H4 Epigenome and Reduces Akt Phosphorylation

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