Nuclear matrix-targeting of the osteogenic factor Runx2 is essential for its recognition and activation of the alkaline phosphatase gene

Weng, Jing Jie; Su, Yeu

doi:10.1016/j.bbagen.2012.12.021

Cited by 43 publications

(29 citation statements)

References 39 publications

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“…Interestingly, we also observed increased gene expression levels of the RUNX2 target gene ALPL (53) as well as an increased ALP activity in heterogeneous BMSC/HNSCC spheroids. Our findings are in line with data showing that serum ALP levels in patients with OSCC at advanced stages were significantly higher than in early stages.…”

Section: Discussionmentioning

confidence: 58%

Induction of ALP and MMP9 activity facilitates invasive behavior in heterogeneous human BMSC and HNSCC 3D spheroids

Wessely¹,

Waltera²,

Reichert³

et al. 2019

The FASEB Journal

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Mesenchymal stem cells (MSCs) are multipotent progenitor cells capable of differentiating into adipocytic, osteogenic, chondrogenic, and myogenic lineages. There is growing evidence that MSCs home into the tumor microenvironment attracted by a variety of signals such as chemokines, growth factors, and cytokines. Tumor‐homing stem cells may originate from bone marrow–derived MSCs (BMSCs) or adipose tissue‐derived MSCs. Recent scientific data suggest that MSCs in combination with tumor cells can either promote or inhibit tumorigenic behavior. In head and neck squamous cell carcinoma (HNSCC), BMSCs are reported to be enriched with a potential negative role. Here, we evaluated the effect of BMSCs from 4 different donors in combination with 4 HNSCC cell lines in a 3‐dimensional multicellular spheroid model. Heterogeneous combinations revealed an up‐regulation of gene and protein expression of osteogenic markers runt‐related transcription factor 2 (RUNX2) and alkaline phosphatase (ALP) together with a substantial secretion of matrix metalloproteinase 9. Moreover, heterogenous BMSC/tumor spheroids showed increased invasion compared with homogenous spheroids in a Boyden chamber invasion assay. Furthermore, inhibition of ALP resulted in a substantially decreased spreading of heterogeneous spheroids on laminin‐rich matrix. In summary, our data suggest a prometastatic effect of BMSCs combined with HNSCC.—Wessely, A., Waltera, A., Reichert, T. E., Stöckl, S., Grässel, S., Bauer, R. J. Induction of ALP and MMP9 activity facilitates invasive behavior in heterogeneous human BMSC and HNSCC 3D‐spheroids. FASEB J. 33, 11884–11893 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 58%

Induction of ALP and MMP9 activity facilitates invasive behavior in heterogeneous human BMSC and HNSCC 3D spheroids

Wessely¹,

Waltera²,

Reichert³

et al. 2019

The FASEB Journal

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“…We noticed that the activities of both ALP and MMP-13 are elevated in ESET-null articular cartilage, and both genes are well known downstream targets of Runx2 protein (25)(26)(27). In our recent studies to understand the molecular FIGURE 6.…”

Section: Discussionmentioning

confidence: 99%

Mesenchyme-specific Knockout of ESET Histone Methyltransferase Causes Ectopic Hypertrophy and Terminal Differentiation of Articular Chondrocytes

Lawson

Teteak

Zou

et al. 2013

Journal of Biological Chemistry

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Background: Articular chondrocytes are responsible for producing articular cartilage and do not normally enter into terminal differentiation. Results: Conditional knock-out of ESET histone methyltransferase results in hypertrophy, apoptosis, and terminal differentiation of articular chondrocytes. Conclusion: ESET is essential for the normal maintenance of articular cartilage and joint function in adult animals. Significance: Learning regulatory mechanisms of articular chondrocytes is critical to the understanding of joint diseases.

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“…Signaling involved in osteo-/chondrogenic differentiation of VSMCs include up-regulation of CBFA1/ RUNX2 (Core-binding factor α1), an osteogenic transcription factor [10] orchestrating the transformation of VSMCs into osteoblast-like cells [11][12][13]. CBFA1-dependent genes include the alkaline phosphatase [12,[14][15][16], which degrades the calcification inhibitor pyrophosphate [10,17]. CBFA1 expression is up-regulated by the TGFß1-sensitive [18] transcription factor NFAT5 (nuclear factor of activated T-cells 5) [19], an effect involving the transcription factor SOX9 [19].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Phosphate-Induced Vascular Smooth Muscle Cell Osteo-/Chondrogenic Signaling and Calcification by Bafilomycin A1 and Methylamine

Alesutan

Musculus

Castor

et al. 2015

Kidney Blood Press Res

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Background/Aims: Excessive phosphate concentrations trigger vascular calcification, an active process promoted by osteoinduction of vascular smooth muscle cells (VSMCs) with increased expression and activity of transcription factor RUNX2 (Core-binding factor α1, CBFA1), alkaline phosphatase (ALPL), TGFß1, transcription factor NFAT5, and NFAT5-sensitive transcription factor SOX9. The osteoinductive signaling and vascular calcification of hyperphosphatemic klotho-hypomorphic mice could be reversed by treatment with NH₄Cl, effects involving decrease of TGFß1 and inhibition of NFAT5-dependent osteoinductive signaling. Known effects of NH₄Cl include alkalinization of acidic cellular compartments. The present study explored whether osteo-/chondrogenic signaling could be influenced by alkalinization of acidic cellular compartments following inhibition of the vacuolar H⁺ ATPase with bafilomycin A1 or following dissipation of the pH gradient across the membranes of acidic cellular compartments with methylamine. Methods: Primary human aortic smooth muscle cells (HAoSMCs) were treated with high phosphate to trigger osteo-/chondrogenic signaling and calcification in the absence or presence of bafilomycin A1 or methylamine. Calcium content was determined using a QuantiChrom Calcium assay, ALP activity by a colorimetric assay and transcript levels by quantitative RT-PCR. Results: High phosphate increased significantly the calcium deposition, CBFA1 and ALPL mRNA expression as well as alkaline phosphatase activity in HAoSMCs, all effects ameliorated by both, bafilomycin A1 and methylamine. High phosphate further significantly up-regulated the mRNA levels of TGFB1, NFAT5 and SOX9, effects significantly blunted by additional treatment with bafilomycin A1 or methylamine. Treatment of HAoSMCs with human TGFß1 protein or high phosphate up-regulated NFAT5, SOX9, CBFA1 and ALPL mRNA expression to similarly high levels which could not be further increased by combined treatment with high phosphate and TGFß1. Bafilomycin A1 failed to reverse the osteo-/chondrogenic signaling triggered by high phosphate together with TGFß1. Conclusions: Inhibition of the vacuolar H⁺ ATPase or dissipation of the pH gradient across the membranes of acidic cellular compartments both disrupt osteo-/chondrogenic signaling and calcium deposition in VSMCs, observations supporting the hypothesis that vascular calcification requires acidic cellular compartments.

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Nuclear matrix-targeting of the osteogenic factor Runx2 is essential for its recognition and activation of the alkaline phosphatase gene

Cited by 43 publications

References 39 publications

Induction of ALP and MMP9 activity facilitates invasive behavior in heterogeneous human BMSC and HNSCC 3D spheroids

Induction of ALP and MMP9 activity facilitates invasive behavior in heterogeneous human BMSC and HNSCC 3D spheroids

Mesenchyme-specific Knockout of ESET Histone Methyltransferase Causes Ectopic Hypertrophy and Terminal Differentiation of Articular Chondrocytes

Inhibition of Phosphate-Induced Vascular Smooth Muscle Cell Osteo-/Chondrogenic Signaling and Calcification by Bafilomycin A1 and Methylamine

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