The Effects of Class-Specific Histone Deacetylase Inhibitors on the Development of Limbs During Organogenesis

Paradis, France-Hélène; Hales, Barbara F.

doi:10.1093/toxsci/kfv174

Cited by 22 publications

(11 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These favorable outcomes may be due to the ability of HDAC inhibitors to neutralize leukocyte populations that are major sources of inflammatory cytokines and chemokines (74–78). However, evidence that HDAC inhibitors have detrimental effects on the developing skeleton also exists (27–31). This study demonstrates that endochondral ossification was unfavorably affected in a number of ways by HDAC3 depletion in growth plate chondrocytes.…”

Section: Discussionmentioning

confidence: 99%

Histone deacetylase 3 supports endochondral bone formation by controlling cytokine signaling and matrix remodeling

et al. 2016

View full text Add to dashboard Cite

Histone deacetylase (HDAC) inhibitors are efficacious epigenetic-based therapies for some cancers and neurological disorders; however, each of these drugs inhibits multiple HDACs and has detrimental effects on the skeleton. To better understand how HDAC inhibitors affect endochondral bone formation, we conditionally deleted one of their targets, Hdac3, pre- and postnatally in type II collagen α1 (Col2α1)–expressing chondrocytes. Embryonic deletion was lethal, but postnatal deletion of Hdac3 delayed secondary ossification center formation, altered maturation of growth plate chondrocytes, and increased osteoclast activity in the primary spongiosa. HDAC3-deficient chondrocytes exhibited increased expression of cytokine and matrix-degrading genes (Il-6, Mmp3, Mmp13, and Saa3) and a reduced abundance of genes related to extracellular matrix production, bone development, and ossification (Acan, Col2a1, Ihh, and Col10a1). Histone acetylation increased at and near genes that had increased expression. The acetylation and activation of nuclear factor κB (NF-κB) were also increased in HDAC3-deficient chondrocytes. Increased cytokine signaling promoted autocrine activation of Janus kinase (JAK)–signal transducer and activator of transcription (STAT) and NF-κB pathways to suppress chondrocyte maturation, as well as paracrine activation of osteoclasts and bone resorption. Blockade of interleukin-6 (IL-6)–JAK–STAT signaling, NF-κB signaling, and bromodomain extraterminal proteins, which recognize acetylated lysines and promote transcriptional elongation, significantly reduced Il-6 and Mmp13 expression in HDAC3-deficient chondrocytes and secondary activation in osteoclasts. The JAK inhibitor ruxolitinib also reduced osteoclast activity in Hdac3 conditional knockout mice. Thus, HDAC3 controls the temporal and spatial expression of tissue-remodeling genes and inflammatory responses in chondrocytes to ensure proper endochondral ossification during development.

show abstract

Section: Discussionmentioning

confidence: 99%

Histone deacetylase 3 supports endochondral bone formation by controlling cytokine signaling and matrix remodeling

et al. 2016

View full text Add to dashboard Cite

show abstract

“…At bone gene enhancers, HDAC3 may function in part through the transcription factors RUNX2 and zinc-finger protein 521 and yet unknown nuclear receptors, resulting in complex and temporal effects in bone and cartilage 143–145 . The phenotypes caused by loss of HDAC3 may in part explain the axial and cranial skeletal defects and predisposition to bone fractures observed with the use of HDAC inhibitors 146–153 .…”

Section: Tissue-specific Functions Of Hdac3mentioning

confidence: 99%

Integrative regulation of physiology by histone deacetylase 3

Emmett

Lazar

2018

Nat Rev Mol Cell Biol

143

118

View full text Add to dashboard Cite

Cell-type-specific gene expression is physiologically modulated by the binding of transcription factors to genomic enhancer sequences, to which chromatin modifiers such as histone deacetylases (HDACs) are recruited. Drugs that inhibit HDACs are in clinical use but lack specificity. HDAC3 is a stoichiometric component of nuclear receptor co-repressor complexes whose enzymatic activity depends on this interaction. HDAC3 is required for many aspects of mammalian development and physiology, for example, for controlling metabolism and circadian rhythms. In this Review, we discuss the mechanisms by which HDAC3 regulates cell type-specific enhancers, the structure of HDAC3 and its function as part of nuclear receptor co-repressors, its enzymatic activity and its post-translational modifications. We then discuss the plethora of tissue-specific physiological functions of HDAC3.

show abstract

“…Whole genome analysis of gene expression changes in murine tissue treated with VPA revealed changes in several ontological groups, including those in the HDAC complex, guanosine triphosphatases, cell proliferation, and cytoskeleton-lending credence to many of the proposed mechanisms listed above (Massa et al, 2005). VPA and epigenetic activity have been shown to regulate as well (Aulthouse and Hitt, 1994;Furumatsu and Ozaki, 2010;Bradley et al, 2015;Paradis and Hales, 2015). The exact relationship of these different mechanisms in producing the reported spectrum of defects has yet to be elucidated.…”

Section: Anticonvulsant Drugsmentioning

confidence: 99%

Prenatal exposure to environmental factors and congenital limb defects

Alexander

Clark

Tuan

2016

Birth Defects Research Pt C

View full text Add to dashboard Cite

Limb congenital defects afflict approximately 0.6:1000 live births. In addition to genetic factors, prenatal exposure to drugs and environmental toxicants, represents a major contributing factor to limb defects. Examples of well-recognized limb teratogenic agents include thalidomide, warfarin, valproic acid, misoprostol, and phenytoin. While the mechanism by which these agents cause dymorphogenesis is increasingly clear, prediction of the limb teratogenicity of many thousands of as yet uncharacterized environmental factors (pollutants) remains inexact. This is limited by the insufficiencies of currently available models. Specifically, in vivo approaches using guideline animal models have inherently deficient predictive power due to genomic and anatomic differences that complicate mechanistic comparisons. On the other hand, in vitro two-dimensional (2D) cell cultures, while accessible for cellular and molecular experimentation, do not reflect the three-dimensional (3D) morphogenetic events in vivo nor systemic influences. More robust and accessible models based on human cells that accurately replicate specific processes of embryonic limb development are needed to enhance limb teratogenesis prediction and to permit mechanistic analysis of the adverse outcome pathways. Recent advances in elucidating mechanisms of normal development will aid in the development of process-specific 3D cell cultures within specialized bioreactors to support multicellular microtissues or organoid constructs that will lead to increased understanding of cell functions, cell-to-cell signaling, pathway networks, and mechanisms of toxicity. The promise is prompting researchers to look to such 3D microphysiological systems to help sort out complex and often subtle interactions relevant to developmental malformations that would not be evident by standard 2D cell culture testing. Birth Defects Research (Part C) 108:243-273, 2016. © 2016 Wiley Periodicals, Inc.

show abstract

The Effects of Class-Specific Histone Deacetylase Inhibitors on the Development of Limbs During Organogenesis

Cited by 22 publications

References 37 publications

Histone deacetylase 3 supports endochondral bone formation by controlling cytokine signaling and matrix remodeling

Histone deacetylase 3 supports endochondral bone formation by controlling cytokine signaling and matrix remodeling

Integrative regulation of physiology by histone deacetylase 3

Prenatal exposure to environmental factors and congenital limb defects

Contact Info

Product

Resources

About