Metal ions induce bone-resorbing cytokine production through the redox pathway in synoviocytes and bone marrow macrophages

Yasuo Niki, Hideo Matsumoto, Yasunori Suda, Toshiro Otani, Kyosuke Fujikawa, Yoshiaki Toyama, Noriyuki Hisamori, Akira Nozue

Research output: Contribution to journalArticlepeer-review

69 Citations (Scopus)


To evaluate the biological reactions to metal ions potentially released from prosthetic implants, we examined the ability of metal ions to produce bone-resorbing cytokines and the underlying mechanism using synoviocytes and bone marrow (BM) macrophages. The cells were incubated with NiCl2, CoCl2, CrCl3 or Fe2(SO4)3 at optimal concentrations, which are detectable in joint fluid following total joint arthroplasty. The production of interleukin-1β, interleukin-6 and tumor necrosis factor-α were enhanced by all metal ions tested as determined by enzyme-linked immunosorbent assay. From the results of electrophoresis mobility shift assay, all metal ions enhanced the DNA-binding activity of nuclear factor κB (NF-κB), and p50-p65 heterodimers and p50 homodimers were the major subunits. These effects of the metal ions were considerably blocked by pyrrolidine dithiocarbamate (PDTC) known as a radical scavenger. An electron spin resonance study clearly demonstrated the ability of metal ions to generate activated oxygen species (AOS), especially hydroxyl radicals (·OH), which accounts for PDTC-blockade of metal ion-induced NF-κB activation and subsequent cytokine production. Taken together, our data raised the possibility that small amounts of metal ions released from prosthetic implants activate synoviocytes and BM macrophages through the AOS-mediated process (i.e. the redox pathway), and contribute to the initiation of osteolysis at the bone-implant interface.

Original languageEnglish
Pages (from-to)1447-1457
Number of pages11
Issue number8
Publication statusPublished - 2003 Apr


  • Activated oxygen species
  • Bone-resorbing cytokines
  • Macrophages
  • Metal ions
  • Redox pathway
  • Synoviocytes

ASJC Scopus subject areas

  • Bioengineering
  • Ceramics and Composites
  • Biophysics
  • Biomaterials
  • Mechanics of Materials


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