Zoledronic acid regulates the synthesis and secretion of IL-1β through Histone methylation in macrophages.
Epigenetics
Inflammation
Journal
Cell death discovery
ISSN: 2058-7716
Titre abrégé: Cell Death Discov
Pays: United States
ID NLM: 101665035
Informations de publication
Date de publication:
2020
2020
Historique:
received:
09
01
2020
revised:
25
04
2020
accepted:
29
04
2020
entrez:
23
6
2020
pubmed:
23
6
2020
medline:
23
6
2020
Statut:
epublish
Résumé
Long-term administration of nitrogen-containing bisphosphonates increases the risk of detrimental side effects, such as bisphosphonate-related osteonecrosis of the jaw (BRONJ). BRONJ development is associated with inflammation, but its pathophysiology remains unknown. Here, we examined whether histone methylation is responsible for zoledronic acid (Zol)-induced inflammatory responses. We found that Kdm6a and Kdm6b markedly increased interleukin 1β expression and Gasdermin D cleavage, which are both activated by Caspase 1, in macrophages. Inhibitors of Kdm6a and Kdm6b robustly abolished Zol-enhanced interleukin 1β synthesis and secretion from macrophages. When Kdm6a and Kdm6b were pharmacologically inhibited in vivo, poor healing of the alveolar socket and inflammatory responses were ameliorated in Zol-treated mice. Taken together, we showed the pathologic role of Kdm6a and Kdm6b in Zol-promoted inflammatory responses and demonstrated that Kdm6a and Kdm6b are potential therapeutic targets for the treatment of BRONJ.
Identifiants
pubmed: 32566254
doi: 10.1038/s41420-020-0273-4
pii: 273
pmc: PMC7289826
doi:
Types de publication
Journal Article
Langues
eng
Pagination
47Informations de copyright
© The Author(s) 2020.
Déclaration de conflit d'intérêts
Conflict of interestThe authors declare no conflict of interest.
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