Fluid pressure induces osteoclast differentiation comparably to titanium particles but through a molecular pathway only partly involving TNFa

• In contrast to the well-understood inflammatory pathway driven by TNFa, by which implant-derived particles induce bone resorption, little is known about the process in which loosening is generated as a result of force-induced mechanical stimulus at the boneimplant interface. Specifically, there is no knowledge as to what cells or signaling pathways couple mechanical stimuli to bone resorption in context of loosening. We hypothesized that different stimuli, i.e., fluid flow versus wear particles, act through different cytokine networks for activation and localization of osteoclasts. By using an animal model in which osteoclasts and bone resorption were induced by fluid pressure or particles, we were able to detect distinct differences in osteoclast localization and inflammatory gene expression between fluid pressure and titanium particles. Fluid pressure recruits and activates osteoclasts with bone marrow contact away from the fluid pressure exposure zone, whereas titanium particles recruit and activate osteoclasts in areas in direct contact to particles. Fluid pressure induced weaker expression of the selected inflammatory related genes, although the eventual degree of osteoclast induction was similar in both models. Using TNFaRa (4?mg/kg) (Enbrel) and dexamethasone (2?mg/kg) as specific and more general suppressors of inflammation we showed that the TNFaRa failed to generate statistically impaired osteoclast generation while dexamethasone was much more potent. These results demonstrate that fluid pressure induces osteoclasts at a different localization than titanium particles by a molecular pathway less associated with TNFa and the innate system, which open up for other pathways controlling pressure induced osteoclastogenesis.

Nyckelord

PRESSURE; FLOW; OSTEOCLASTOGENESIS; CYTOKINES; OSTEOLYSIS

MEDICINE

MEDICIN

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