Abstract
N,N-Dimethylacetamide (DMA) is a water-miscible solvent, FDA approved as excipient and therefore widely used as drug-delivery vehicle. As such, DMA should be devoid of any bioactivity. Here we report that DMA is epigenetically active since it binds bromodomains and inhibits osteoclastogenesis and inflammation. Moreover, DMA enhances bone regeneration in vivo. Therefore, our in vivo and in vitro data reveal DMA’s potential as an anti-osteoporotic agent via the inhibition of osteoclast mediated bone resorption and enhanced bone regeneration. Our results highlight the potential therapeutic benefits of DMA and the need for reconsideration of previous reports where DMA was used as an ‘inactive’ drug-delivery vehicle.
Highlights
Heritable changes in gene expression or cellular phenotype not linked to changes in the underlying DNA sequence are studied in epigenetics
Despite the fact that DMA concentrations needed for bromodomain inhibition are in the mM-range, this effect is meaningful since during busulfan administration, DMA concentrations found in serum ranges between 3.09 and 8.77 mM20
Since nuclear factor-κB (NF-κB) is involved in the transcriptional regulation of cytokines and targeted by bromodomain inhibitors, we examined the nuclear translocation of p65 which tightly linked to NFκB activation
Summary
Heritable changes in gene expression or cellular phenotype not linked to changes in the underlying DNA sequence are studied in epigenetics Such changes include acetylation known to act as scaffolds for the assembly of macromolecular complexes that orchestrate chromatin accessibility to transcription factors and allow the recruitment and activation of the RNA polymerases. A link between bromodomains and the immune system has been shown for Brd[4] and NFĸB with its two subunits p50 and RelA5 The latter subunit, if acetylated, binds Brd[4], which in turn enhances the transcriptional activation of NF-ĸB and the expression of a subset of NF-ĸB-responsive inflammatory genes. Osteoporosis is a skeletal disorder characterized by compromised bone strength associated to an increase in fracture risk It is most often caused by osteoclastic bone resorption that is not sufficiently compensated for by increased bone formation by osteoblasts[12]. This study focuses on the potential therapeutic benefits of DMA in osteoporosis, bone regeneration and related bone diseases, and emphasizes the fact that studies where DMA or other solvents were used as controls must be analyzed with caution
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