Titanium particles stimulate bone resorption by inducing differentiation of murine osteoclasts

Background: Loosening of orthopaedic implants is mediated by cytokines that elicit bone resorption and are produced in response to phagocytosis of imp lant-derived wear particles. This accelerated bone resorption could be due to increased osteoclastic activity, survival, or differentiation. Although a number of in vitro studies have shown that wear particles increase osteoc lastic activity, the increase was less than twofold in all cases. The objec tive of the current study was to test the hypothesis that wear particles st imulate bone resorption by inducing osteoclast differentiation. Methods: Conditioned media were prepared from murine marrow cells or human peripheral blood monocytes incubated in the presence or absence of titanium particles. The effects of conditioned media on osteoclast differentiation were examined with use of a recently developed assay in which osteoclast pr ecursors are co-cultured with mesenchymal support cells. Results: The present study showed that titanium particles induced both muri ne marrow cells and human peripheral blood monocytes to produce factors tha t stimulated osteoclast differentiation. The mean increase in osteoclast di fferentiation was 29.3 +/- 9.4-fold. The stimulation of osteoclast differen tiation led to a parallel increase in bone resorption. The amount of stimul ation was regulated in a dose-dependent manner by the concentration of both titanium particles and conditioned media. The stimulation of osteoclast di fferentiation required interactions between the cells and the particles the mselves and, therefore, was not due to metal ions, soluble contaminants rel eased from the particles, or submicrometer particles. In contrast, conditio ned media from control cells incubated in the absence of titanium particles had no detectable effect on any of the examined parameters. Conclusions: The present study showed that titanium particles stimulate in vitro bone resorption primarily by inducing osteoclast differentiation. In contrast, the titanium particles had only small effects on osteoclast activ ity or survival. Clinical Relevance: The present study provides strong support for the hypot hesis that osteoclast differentiation is an important factor in the develop ment of aseptic loosening. The development of therapeutic interventions to reduce osteoclast differentiation may be a useful approach for improving th e performance of orthopaedic implants.