Effects of zoledronate on local and systemic production of IL-1β, IL- 18, and TNF-α in mice and augmentation by lipopolysaccharide

Hiromi Funayama, Itaru Tashima, Satoru Okada, Takuya Ogawa, Hideki Yagi, Hiroyuki Tada, Ryo Wakita, Yoshinobu Asada, Yasuo Endo

Research output: Contribution to journalArticlepeer-review

10 Citations (Scopus)


Bisphosphonates (BPs) containing nitrogen (N-BPs) exhibit far stronger anti-bone-resorptive effects than non-N-BPs. However, repeated administration of N-BPs causes osteonecrosis selectively in jawbones. As BPs accumulate in large amounts within inflamed bones, any N-BP released from the pool accumulated within jawbones might directly act on cells in the surrounding soft-tissues and induce inflammation or necrosis. Here, we examined the local and systemic effects of zoledronate (the most potent N-BP with the highest incidence of jawbone-necrosis) on inflammatory cytokines in mice. Locally within ear-pinnas: (i) zoledronate induced long-lasting accumulation of interleuikin-1β (IL-1β) and IL-18, but not tumor necrosis factor-α (TNF-α), (ii) zoledronate and lipopolysaccharide (LPS, a cell-wall component of Gram-negative bacteria) mutually augmented the productions of IL-1β, IL-18, and TNF-α, and (iii) oxidronate (a toxic non-N-BP) by itself produced not only IL-1β and IL-18, but also TNF-α. In systemic experiments using intraperitoneal injection of zoledronate and/or LPS, (i) zoledronate by itself increased none of the above cytokines in serum, and (ii) in mice pretreated (3 d before) with zoledronate, the LPS-induced increases in serum IL-1β and IL-18 were greatly augmented with a delayed slight TNF-α augmentation. These results, together with previous ones, suggest that (a) pro-IL-1β and pro-IL-18 accumulate within cells in soft-tissues exposed to N-BPs, and infection may augment not only their production, but also the release of their mature forms, (b) IL-1β and IL-18 (possibly together with TNF-α) may play important roles in N-BP-induced inflammation and/or necrosis, and (c) mechanisms underlying the cytotoxic effects of BPs may differ between N-BPs and non-N-BPs.

Original languageEnglish
Pages (from-to)929-936
Number of pages8
JournalBiological and Pharmaceutical Bulletin
Issue number6
Publication statusPublished - 2019


  • Bisphosphonate
  • Interleuikin-1 (IL-1)
  • Interleukin-18 (IL-18)
  • Lipopolysaccharide
  • Tumor necrosis factor-α (TNF-α)
  • Zoledronate


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