Abstract
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.
Highlights
Bisphosphonates (BPs) are highly associated with bone minerals and exhibit potent anti-bone-resorptive effects
To investigate whether histone methylation plays a role in the zoledronic acid (Zol)-induced inflammatory responses, RAW264.7 macrophages were stimulated with vehicle or 25 μg/ml Zol
These findings suggest that the upregulation of Kdm6a and Kdm6b in macrophages is indispensable for Zolenhanced Caspase 1 and IL-1β activation
Summary
Bisphosphonates (BPs) are highly associated with bone minerals and exhibit potent anti-bone-resorptive effects. Since reported by Marx in 20032, bisphosphonate-related osteonecrosis of the jaw (BRONJ) has emerged as a serious side effect of BP treatment, especially nitrogen-containing bisphosphonates (NBPs), such as zoledronic acid (Zol)[3]. Risk factors such as operative treatment, concomitant oral disease, chemotherapeutics, anti-angiogenic agents and steroids are related to the pathogenesis of BRONJ4. Caspase 1 activation and IL-1β production in macrophages contribute to the development of BRONJ1,4. When macrophages are stimulated by pathogen-associated molecular patterns and damage-associated molecular patterns, protein complexes called inflammasomes are induced that recruit pro-Caspase 1 and result in its proximity-mediated auto-proteolysis. IL-1β and IL-18 are released extracellularly to stimulate inflammatory
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