Effect of the HDAC inhibitor vorinostat on the osteogenic differentiation of mesenchymal stem cells in vitro and bone formation in vivo

Xu, Song; Veirman, Kim De; Evans, Holly; Santini, Gaia; Broek, Isabelle Vande; Leleu, Xavier; Becker, Ann De; Camp, Benjamin Van; Croucher, Peter I.; Vanderkerken, Karin; Riet, Ivan Van

doi:10.1038/aps.2012.182

Cited by 53 publications

(50 citation statements)

References 42 publications

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“…Nevertheless, our observations appear to be in contrast with previous works in which a positive effect of these drugs on RUNX2 expression was reported in skeletal cells (43,44). Currently, there are no experimental data to explain such discrepancy, but the different cellular context is likely to play a relevant role.…”

Section: Discussioncontrasting

confidence: 99%

Histone Deacetylase Inhibitors Repress Tumoral Expression of the Proinvasive Factor RUNX2

Sancisi¹,

Gandolfi²,

Ambrosetti

et al. 2015

Cancer Research

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Aberrant reactivation of embryonic pathways occurs commonly in cancer. The transcription factor RUNX2 plays a fundamental role during embryogenesis and is aberrantly reactivated during progression and metastasization of different types of human tumors. In this study, we attempted to dissect the molecular mechanisms governing RUNX2 expression and its aberrant reactivation. We identified a new regulatory enhancer element, located within the RUNX2 gene, which is responsible for the activation of the RUNX2 promoter and for the regulation of its expression in cancer cells. Furthermore, we have shown that treatment with the anticancer compounds histone deacetylase inhibitor (HDACi) results in a profound inhibition of RUNX2 expression, which is determined by the disruption of the transcription-activating complex on the identified enhancer. These data envisage a possible targeting strategy to counteract the oncongenic function of RUNX2 in cancer cells and provide evidence that the cytotoxic activity of HDACi in cancer is not only dependent on the reactivation of silenced oncosuppressors but also on the repression of oncogenic factors that are necessary for survival and progression.Cancer Res; 75(9); 1868-82. Ó2015 AACR.

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Section: Discussioncontrasting

confidence: 99%

Histone Deacetylase Inhibitors Repress Tumoral Expression of the Proinvasive Factor RUNX2

Sancisi¹,

Gandolfi²,

Ambrosetti

et al. 2015

Cancer Research

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“…Selective targeting and lower doses (10-100x lower) of HDACi have been shown to be better tolerated in animal models and have different effects on bone cells without the induction of apoptosis. This is supported by a recent in vitro study demonstrating that higher doses of vorinostat induced apoptosis of mesenchymal stem cells, but was not observed when lower doses were used [78].…”

Section: General Effects Of Hdaci On Bone Formationsupporting

confidence: 52%

Histone deacetylases (HDAC) in physiological and pathological bone remodelling

Cantley

Zannettino

Bartold

et al. 2017

Bone

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Histone deacetylases (HDACs) 1 play important roles in the epigenetic regulation of gene expression in cells and are emerging therapeutic targets for treating a wide range of diseases. HDAC inhibitors (HDACi) 2 that act on multiple HDAC enzymes have been used clinically to treat a number of solid and hematological malignancies. HDACi are currently being studied also for their efficacy in nonmalignant diseases, including pathologic bone loss, but this has necessitated a better understanding of the roles of individual HDAC enzymes, particularly the eleven zinc-containing isozymes.Selective isozyme-specific inhibitors currently being developed against class I HDAC (1, 2, 3 and 8) and class II HDAC (4, 5, 6, 7, 9 and 10) will be valuable tools for elucidating the roles played by individual HDACs in different physiological and pathological settings. Isozyme-specific HDACi promise to have greater efficacy and reduced side effects, as required for treating chronic disease over extended periods of time. This article reviews the current understanding of roles for individual HDAC isozymes and effects of HDACi on bone cells, (osteoblasts, osteoclasts and osteocytes), in relation to bone remodelling in conditions characterised by pathological bone loss, including periodontitis, rheumatoid arthritis and myeloma bone disease.

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“…Paradoxically, while osteoblast numbers were reduced in vorinostat treated bones, measures of osteoblast activity such as mineral apposition rate and bone formation rate were elevated. In vitro studies showed that immature osteoblasts were highly susceptible to DNA damage and cell cycle arrest when cultured in the presence of vorinostat [89, 90]. …”

Section: Introductionmentioning

confidence: 99%

“…However, the direct effects of the drugs on precursor cells remain a concern for in vivo bone regeneration [75]. Although some studies suggest that systemic administration of vorinostat at lower doses or reduced frequency may prevent the adverse skeletal effects of HDI therapy [90], finding an effective dose of a broad acting histone modifying drug that has no effects on a renewing tissue like bone, blood, or gastric epithelium may be impossible, just as it is for many cancer therapies, including chemotherapy and hormone-deprivation, and anti-inflammatory medications (e.g., corticosteroids). One way to address this problem is to gain a better understanding of which epigenetic modulators (readers, writers, and erasers) are expressed in bone cells so that more specific inhibitors can be designed for specific diseases.…”

Section: Introductionmentioning

confidence: 99%

Chromatin modifiers and histone modifications in bone formation, regeneration, and therapeutic intervention for bone-related disease

Gordon

Stein

Westendorf

et al. 2015

Bone

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Post-translational modifications of chromatin such as DNA methylation and different types of histone acetylation, methylation and phosphorylation are well-appreciated epigenetic mechanisms that confer information to progeny cells during lineage commitment. These distinct epigenetic modifications have defined roles in bone, development, tissue regeneration, cell commitment and differentiation, as well as disease etiologies. In this review, we discuss the role of these chromatin modifications and the enzymes regulating these marks (methyltransferases, demethylases, acetyltransferases, and deacetylases) in progenitor cells, osteoblasts and bone-related cells. In addition, the clinical relevance of deregulated histone modifications and enzymes as well as current and potential therapeutic interventions targeting chromatin modifiers are addressed.

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Effect of the HDAC inhibitor vorinostat on the osteogenic differentiation of mesenchymal stem cells in vitro and bone formation in vivo

Abstract: Vorinostat, known as a potent anti-myeloma drug, stimulates MSC osteogenesis in vitro. With the optimized treatment regimen, any decrease in bone formation was not observed in vivo.

Cited by 53 publications

References 42 publications

Histone Deacetylase Inhibitors Repress Tumoral Expression of the Proinvasive Factor RUNX2

Histone Deacetylase Inhibitors Repress Tumoral Expression of the Proinvasive Factor RUNX2

Histone deacetylases (HDAC) in physiological and pathological bone remodelling

Chromatin modifiers and histone modifications in bone formation, regeneration, and therapeutic intervention for bone-related disease

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