Titanium and zirconia particle-induced pro-inflammatory gene expression in cultured macrophages and osteolysis, inflammatory hyperalgesia and edema in vivo

Life Sci. 2014 Mar 3;97(2):96-106. doi: 10.1016/j.lfs.2013.11.008. Epub 2013 Nov 16.


Aims: The biological reaction to wear debris is critical to the osteolysis underlying aseptic loosening of joint prosthetic implants. In an attempt to reduce aseptic loosening, ceramics have been introduced. This study was designed to evaluate, compare and correlate the expression of Toll-like receptors (TLRs), their intracellular adaptors and proinflammatory cytokines in cultured macrophages challenged with titanium or zirconia particles, as well as particle-induced osteolysis in calvaria and hyperalgesia and edema in hind paw.

Main methods: TLRs and their adaptors were evaluated at the mRNA level by RT-PCR, and cytokine expression was evaluated at the mRNA and protein levels. Osteolysis and hyperalgesia and edema were evaluated in vivo, in calvaria and hind paw, respectively.

Key findings: Cultured macrophages challenged with zirconia or titanium particles expressed increased mRNA for TLRs 2, 3, 4 and 9, and their adaptors MyD88, TRIF and NF-κB and cytokines TNF-α, IL-1β and IL-6, which were also increased at protein level. Quantitative differences are evident and, in general, zirconia particle-induced pro-inflammatory gene expression was lower than that induced by titanium particles. In in vivo experiments, exposition to titanium or zirconia particles induced osteolysis in calvaria and hyperalgesia and edema in hind paw; however those induced by zirconia particles were significantly lower. There is a strong and positive correlation between the expressions of mRNA for TLR4, NF-κB, TNF-α, IL-1β and IL-6.

Significance: Collectively, our data suggest that zirconia ceramic particles are less bioactive than titanium particles.

Keywords: Aseptic loosening; Cytokines; Macrophage; Osteolysis; Titanium particles; Toll-like receptors; Zirconia particles.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Cytokines / metabolism
  • Edema / chemically induced*
  • Gene Expression Regulation / drug effects
  • Hyperalgesia / chemically induced*
  • Inflammation / chemically induced*
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Osteolysis / chemically induced
  • RNA, Messenger / metabolism
  • Skull / drug effects
  • Skull / metabolism
  • Titanium / toxicity*
  • Toll-Like Receptors / genetics
  • Zirconium / toxicity*


  • Cytokines
  • RNA, Messenger
  • Toll-Like Receptors
  • Zirconium
  • Titanium
  • zirconium oxide