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Epigenetic drugs as new therapy for tumor necrosis factor-α-compromised bone healing


Chen, Tse-Hsiang; Weber, Franz E; Malina-Altzinger, Johann; Ghayor, Chafik (2019). Epigenetic drugs as new therapy for tumor necrosis factor-α-compromised bone healing. Bone, 127:49-58.

Abstract

Impaired bone regeneration by excess inflammation leads to failure of bone healing. Current therapies display limited benefits making new treatments imperative. Our recent discoveries of the anti-inflammatory characteristics of bromodomain and extra terminal domain (BET) inhibitors, N-methylpyrrolidone (NMP) and N,N-Dimethylacetamide (DMA), implicate possible therapeutic use of epigenetic drugs in inflammation-impaired bone healing.
Here, we investigated the effects of NMP and DMA on osteogenesis in vitro and ex vivo under the influence of TNFα, a key cytokine responsible for impaired fracture healing. NMP and DMA pre-treatment recovered TNFα-inhibited expression of essential osteoblastic genes, Alp, Runx2, and Osterix as well as mineralization in multipotent stem cells, but not in pre-osteoblasts and calvarial osteoblasts. The mechanism of action involves the recovery of TNFα-suppressed BMP-induced Smad signaling and the reduction of TNFα-triggered ERK pathway. In addition, ERK inhibitor treatment diminished the effect of TNFα on osteogenesis, which reinforces the role of ERK pathway in the adverse effect of TNFα. Furthermore, endochondral ossification was analyzed in an ex vivo bone culture model. TNFα largely abrogated BMP-promoted growth of mineralized bone while pre-treatment of NMP and DMA prevented the deleterious effect of TNFα. Taken together, these data shed light on developing low- affinity epigenetic drugs as new therapies for inflammation-compromised bone healing.

Abstract

Impaired bone regeneration by excess inflammation leads to failure of bone healing. Current therapies display limited benefits making new treatments imperative. Our recent discoveries of the anti-inflammatory characteristics of bromodomain and extra terminal domain (BET) inhibitors, N-methylpyrrolidone (NMP) and N,N-Dimethylacetamide (DMA), implicate possible therapeutic use of epigenetic drugs in inflammation-impaired bone healing.
Here, we investigated the effects of NMP and DMA on osteogenesis in vitro and ex vivo under the influence of TNFα, a key cytokine responsible for impaired fracture healing. NMP and DMA pre-treatment recovered TNFα-inhibited expression of essential osteoblastic genes, Alp, Runx2, and Osterix as well as mineralization in multipotent stem cells, but not in pre-osteoblasts and calvarial osteoblasts. The mechanism of action involves the recovery of TNFα-suppressed BMP-induced Smad signaling and the reduction of TNFα-triggered ERK pathway. In addition, ERK inhibitor treatment diminished the effect of TNFα on osteogenesis, which reinforces the role of ERK pathway in the adverse effect of TNFα. Furthermore, endochondral ossification was analyzed in an ex vivo bone culture model. TNFα largely abrogated BMP-promoted growth of mineralized bone while pre-treatment of NMP and DMA prevented the deleterious effect of TNFα. Taken together, these data shed light on developing low- affinity epigenetic drugs as new therapies for inflammation-compromised bone healing.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Center for Dental Medicine > Clinic of Cranio-Maxillofacial Surgery
Dewey Decimal Classification:610 Medicine & health
Scopus Subject Areas:Health Sciences > Endocrinology, Diabetes and Metabolism
Life Sciences > Physiology
Health Sciences > Histology
Language:English
Date:1 October 2019
Deposited On:13 Jan 2020 12:04
Last Modified:29 Jul 2020 12:29
Publisher:Elsevier
ISSN:1873-2763
OA Status:Hybrid
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1016/j.bone.2019.05.035
PubMed ID:31152802
Project Information:
  • : FunderSNSF
  • : Grant ID31003A_140868
  • : Project TitleThe potential of N-methylpyrrolidone to prevent osteoporosis and to enhance bone regeneration
  • : FunderSNSF
  • : Grant IDCR32I3_152809
  • : Project TitleOsteoconductive and osteoinductive customized implants for large mandibular defects

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