The epigenetically active small chemical N-methyl pyrrolidone (NMP) prevents estrogen depletion induced osteoporosis

Gjoksi, Bebeka; Ghayor, Chafik; Siegenthaler, Barbara; Ruangsawasdi, Nisarat; Zenobi‐Wong, Marcy; Weber, Franz E.

doi:10.1016/j.bone.2015.05.004

Cited by 31 publications

(51 citation statements)

References 39 publications

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“…Molecules, like NMP which enhance bone regeneration and suppress osteoclast differentiation [6,7] and inhibit inflammatory mediators as demonstrated in this study strengthens its potential for treating RA, osteoporosis [27] and other inflammatory-related bone diseases.…”

Section: Discussionsupporting

confidence: 60%

“…Furthermore, the binding of Brd4 to acetylated lysine-310 is essential for the recruitment of Brd4 to the promoters of NF-κB target genes and to coactivate NF-κB [31]. Recently we showed that NMP prevents BRD4 from binding acetylated lysine [27]. Here we showed that NMP inhibits NF-κB pathway, most likely by preventing BRD4 binding.…”

Section: Discussionmentioning

confidence: 68%

“…Recently, we showed that NMP acts as a low affinity bromodomain inhibitor and its possible role as clinically applicable candidate for the application of epigenetics as new mechanism for osteoporosis treatment [27]. Epigenetics refers to transmissible changes in gene expression that does not involve changes to the underlying DNA sequence.…”

Section: Discussionmentioning

confidence: 99%

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N-methyl pyrrolidone (NMP) inhibits lipopolysaccharide-induced inflammation by suppressing NF-κB signaling

et al. 2015

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OBJECTIVE: N-methyl pyrrolidone (NMP), a small bioactive molecule, stimulates bone formation and inhibits osteoclast differentiation and bone resorption. The present study was aimed to evaluate the anti-inflammatory potentials of NMP on the inflammatory process and the underlying molecular mechanisms in RAW264.7 macrophages. MATERIALS AND METHODS: RAW264.7 macrophages and mouse primary bone marrow macrophages (mBMMs) were used as an in vitro model to investigate inflammatory processes. Cells were pre-treated with or without NMP and then stimulated with lipopolysaccharides (LPS). The productions of cytokines and NO were determined by proteome profiler method and nitrite analysis, respectively. The expressions of nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) were measured by Western blotting and/or qPCR. Western blot, ELISA-base reporter assay, and immunofluorescence were used to evaluate the activation of MAP kinases and NF-B. RESULTS: LPS-induced mRNA expressions of TNF-, IL-1, IL-6, iNOS, and COX-2 were inhibited by NMP in a dose-dependent manner. NMP also suppressed the LPS-increased productions of iNOS and NO. The proteome profiler array showed that several cytokines and chemokines involved in inflammation and up-regulated by LPS stimulation were significantly down-regulated by NMP. Additionally, this study shows that the effect of NMP is mediated through down-regulation of NFB pathway. CONCLUSIONS: Our results show that NMP inhibits the inflammatory mediators in macrophages by an NFB-dependent mechanism, based on the epigenetical activity of NMP as bromodomain inhibitor. In the light of its action on osteoblast and osteoclast differentiation process and its anti-inflammatory potential, NMP might be used in inflammation-related bone loss. CONCLUSIONS:Our results show that NMP inhibits the inflammatory mediators in macrophages by an NFκB-dependent mechanism, based on the epigenetical activity of NMP as bromodomain inhibitor. In the light of its action on osteoblast and osteoclast differentiation process and its anti-inflammatory potential, NMP might be used in inflammation-related bone loss.

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 68%

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N-methyl pyrrolidone (NMP) inhibits lipopolysaccharide-induced inflammation by suppressing NF-κB signaling

et al. 2015

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“…In this context, we recently showed that, JQ1, one of the BET protein inhibitor was able to suppress osteosarcoma mediated bone remodeling in a preclinical model [11]. Since then, several studies have shown that BET protein inhibition seems to be a potential candidate for the treatment of bone related diseases associated with inflammation [14][15][16].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, these smallmolecule inhibitors of BET proteins were recently identified to suppress bone destruction in many distinct inflammatory diseases (arthritis, periodontitis, bone tumour, osteoporosis) [11,[14][15][16].…”

Section: Accepted M Manuscriptmentioning

confidence: 99%

Inhibition of BET proteins and epigenetic signaling as a potential treatment for osteoporosis

Baud’huin

Lamoureux

Jacques

et al. 2017

Bone

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Histone modifications are important for maintaining the transcription program. BET proteins, an important class of "histone reading proteins", have recently been described as essential in bone biology. This study presents the therapeutic opportunity of BET protein inhibition in osteoporosis. We find that the pharmacological BET protein inhibitor JQ1 rescues pathologic bone loss in a post-ovariectomy osteoporosis model by increasing the trabecular bone volume and restoring mechanical properties. The BET protein inhibition suppresses osteoclast differentiation and activity as well as the osteoblastogenesis in vitro. Moreover, we show that treated non-resorbing osteoclasts could still activate osteoblast differentiation. In addition, specific inhibition of BRD4 using RNA interference inhibits osteoclast differentiation but strongly activates osteoblast mineralization activity. Mechanistically, JQ1 inhibits expression of the master osteoclast transcription factor NFATc1 and the transcription factor of osteoblast Runx2. These findings strongly support that targeting epigenetic chromatin regulators such as BET proteins may offer a promising alternative for the treatment of bone-related disorders such as osteoporosis.

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Ridge preservation of extraction sockets with buccal bone deficiency using poly lactide‐co‐glycolide coated β‐tricalcium phosphate bone grafts: An experimental study in dogs

Okada

Matsuura

Akizuki

et al. 2019

Journal of Periodontology

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Background:The alveolar ridge undergoes pronounced reduction in height and width following tooth extraction. This study aims to comparatively evaluate the potential for ridge preservation in extraction sockets with buccal bone deficiency of -tricalcium phosphate coated with poly lactide-co-glycolide ( -TCP/PLGA) and conventional particulate -TCP. Methods:In six beagles, maxillary first premolars were extracted after removal of their buccal bone plates. Standardized bone defects (4 [mesiodistal width] × 4 [buccopalatal width] × 5 [depth] mm) were created at the sites of extraction sockets and filled with -TCP/PLGA (test sites) or particulate -TCP (control sites). Microcomputed tomography, histologic, and histometric evaluations were performed 12 weeks post-surgery. Results:The test sites exhibited a significantly greater bone volume than the control sites (25.7 ± 2.14 versus 16.0 ± 3.3 mm 3 ), although no statistically significant difference was detected in bone material density (746.3 ± 23.9 versus 714.5 ± 37.0 g/cm 3 , respectively). Relative to the control sites, the test sites exhibited significantly greater alveolar-ridge coronal (2.0 ± 0.4 versus 1.1 ± 0.3 mm) and middle (2.9 ± 0.2 versus 2.1 ± 0.3 mm) horizontal widths and proportions of woven bone (50.3 ± 8.1% versus 38.0 ± 5.2%) and bone marrow (17.7 ± 6.6% versus 9.7 ± 4.1%) but a significantly lower proportion of connective tissue (10.7 ± 4.5% versus 18.3 ± 5.7%). Conclusion:Within the limitations of this study, the moldable -TCP/PLGA graft appears to exhibit a greater potential than the conventional particulate -TCP graft for ridge preservation of extraction sockets with buccal bone deficiency. K E Y W O R D Salveolar ridge augmentation, -tricalcium phosphate, biocompatible materials, dogs, osteogenesis, tooth extraction 1014

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The epigenetically active small chemical N-methyl pyrrolidone (NMP) prevents estrogen depletion induced osteoporosis

Cited by 31 publications

References 39 publications

N-methyl pyrrolidone (NMP) inhibits lipopolysaccharide-induced inflammation by suppressing NF-κB signaling

N-methyl pyrrolidone (NMP) inhibits lipopolysaccharide-induced inflammation by suppressing NF-κB signaling

Inhibition of BET proteins and epigenetic signaling as a potential treatment for osteoporosis

Ridge preservation of extraction sockets with buccal bone deficiency using poly lactide‐co‐glycolide coated β‐tricalcium phosphate bone grafts: An experimental study in dogs

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