Structure-dependent effects of bisphosphonates on inflammatory responses in cultured neonatal mouse calvaria

Keiko Suzuki, Sadaaki Takeyama, Shinobu Murakami, Masahiro Nagaoka, Mirei Chiba, Kaoru Igarashi, Hisashi Shinoda

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)


Bisphosphonates (BPs) are classified into two groups, according to their side chain structures, as nitrogen-containing BPs (NBPs) and non-nitrogen-containing BPs (non-NBPs). In this study, we examined the effects of NBPs and non-NBPs on inflammatory responses, by quantifying the inflammatory mediators, prostaglandin E2 (PGE2) and nitric oxide (NO), in cultured neonatal mouse calvaria. All examined NBPs (pamidronate, alendronate, incadronate, risedronate, zoledronate) stimulated lipopolysaccharide (LPS)-induced PGE2 and NO production by upregulating COX-2 and iNOS mRNA expression, whereas non-NBPs (etidronate, clodronate, tiludronate) suppressed PGE2 and NO production, by downregulating gene expression. Additionally, [4-(methylthio) phenylthio] methane bisphosphonate (MPMBP), a novel non-NBP with an antioxidant methylthio phenylthio group in its side chain, exhibited the most potent anti-inflammatory activity among non-NBPs. Furthermore, results of immunohistochemistry showed that the nuclear translocation of NF-κB/p65 and tyrosine nitration of cytoplasmic protein were stimulated by zoledronate, while MPMBP inhibited these phenomena, by acting as a superoxide anion (O2) scavenger. These findings indicate that MPMBP can act as an efficacious agent that causes fewer adverse effects in patients with inflammatory bone diseases, including periodontitis and rheumatoid arthritis.

Original languageEnglish
Article number503
Pages (from-to)1-18
Number of pages18
Issue number6
Publication statusPublished - 2020 Jun
Externally publishedYes


  • Anti-inflammatory
  • Antioxidant
  • Bisphosphonate
  • Bisphosphonate-related osteonecrosis of the jaw (BRONJ)
  • NF-κB
  • NO
  • Nitrotyrosine
  • PGE
  • Periodontitis
  • Peroxynitrite

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology


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