Mechanisms of orthopaedic wear particle-induced osteolysis

Local bone resorption, termed osteolysis, is the major mechanism of orthopaedic implant loosening. Osteolysis is mediated by bone resorptive cytokines that are produced in response to implant-derived wear particles. The objective of my dissertation is to elucidate the cellular mechanisms of wear particle-induced cell activation and subsequent effects on bone cells.; To determine the primary effect of wear particles on osteoclasts, I have developed an in vitro osteoclast differentiation assay to determine the effect of titanium particle-conditioned media on differentiation, activity, and survival of osteoclasts. The results show that titanium particles induce either murine marrow cells or human peripheral blood monocytes to produce soluble factors that primarily stimulate osteoclast differentiation. The stimulation of osteoclast differentiation leads to a parallel increase in bone resorption. In contrast to the above results, conditioned media from control cells incubated in the absence of titanium particles have no detectable effect on any of the examined parameters.; To study the mechanisms of wear particle-induced activation of cells, the role of adherent endotoxin was examined during wear particle-induced biological responses. The results demonstrate that adherent endotoxin is responsible for particle-induced cytokine production and osteoclast differentiation in vitro, as well as osteolysis in vivo. The induction of cytokine production and osteoclast differentiation by adherent endotoxin in vitro is mediated by Toll-like receptor-4.; In order to investigate whether the mechanism by which adherent endotoxin stimulates cytokine production and osteoclast differentiation is due to increasing phagocytosis of wear particles, a phagocytosis assay was established to examine phagocytosis of titanium particles. The results show that adherent endotoxin does not affect the extent or the rate of phagocytosis of titanium particles.; Taken together, the results shown in this dissertation demonstrate that adherent endotoxin on wear particles is a key player in the induction of bone resorptive cytokines that primarily stimulate osteoclast differentiation, which leads to osteolysis.