Metal ions induce bone-resorbing cytokine production through the redox pathway in synoviocytes and bone marrow macrophages.
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 NiCl(2), CoCl(2), CrCl(3) or Fe(2)(SO(4))(3) at optimal concentrations, which are detectable in joint fluid following total joint arthroplasty. The production of interleukin-1beta, interleukin-6 and tumor necrosis factor-alpha 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 kappaB (NF-kappaB), 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-kappaB 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.
Niki
Yasuo
Y
Department of Orthopaedic Surgery, Keio University, 35, Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. y.niki@lib.bekkoame.ne.jp
Matsumoto
Hideo
H
Suda
Yasunori
Y
Otani
Toshiro
T
Fujikawa
Kyosuke
K
Toyama
Yoshiaki
Y
Hisamori
Noriyuki
N
Nozue
Akira
A
D000328:Adult; D000975:Antioxidants / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D001862:Bone Resorption / Q000139:chemically induced* / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis*; D004247:DNA / Q000378:metabolism; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007375:Interleukin-1 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D007595:Joint Prosthesis / Q000009:adverse effects*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D008297:Male; D008422:Materials Testing; D008670:Metals / Q000633:toxicity*; D008875:Middle Aged; D016328:NF-kappa B / Q000378:metabolism; D010084:Oxidation-Reduction; D011392:Proline / Q000031:analogs & derivatives* / Q000494:pharmacology; D011475:Prosthesis Failure; D017382:Reactive Oxygen Species / Q000378:metabolism; D013583:Synovial Membrane / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013859:Thiocarbamates / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000975:Antioxidants; D016207:Cytokines; D007375:Interleukin-1; D015850:Interleukin-6; D008670:Metals; D016328:NF-kappa B; D017382:Reactive Oxygen Species; D013859:Thiocarbamates; D014409:Tumor Necrosis Factor-alpha; C066229:prolinedithiocarbamate; D004247:DNA; D011392:Proline