CELLULAR MECHANISMS OF IMPLANT LOOSENING

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Aseptic loosening of joint implants is one of the major problems in clinical orthopaedics. We and others have recently provided evidence that adherent endotoxin is involved in the stimulation by wear particles of both cytokine production and osteoclast differentiation. However, the importance of endotoxin in vivo is less well studied. Our proposed studies are, therefore, designed to more conclusively test the over-all hypothesis that adherent endotoxin is an important stimulator of wear particle- induced osteolysis. This hypothesis does not suggest that adherent endotoxin is the only stimulator of osteolysis, only that endotoxin is an important stimulator. The following specific aims are proposed: Aim 1. To determine the mechanism of action of adherent endotoxin in vitro. This aim will test three alternative, but not mutually-exclusive, hypotheses The first hypothesis is that the wear particles deliver endotoxin to the responding cells. The second hypothesis is that adherent endotoxin on the wear particles increases attachment to, and/or phagocytosis by, the responding cells. The third hypotheses is that adherent endotoxin alters the nature of the cellular response to the wear particles. Aim 2. To determine whether adherent endotoxin is an important stimulator of particle-induce osteolysis in vivo. This aim will two complementary hypothesis The first hypothesis is that adherent endotoxin is an important stimulator of wear particle-induced osteolysis in mice. The second hypothesis is that wear particles retrieved from patients with aseptic loosening contain substantial amounts of adherent endotoxin. Aim 3. To determine whether adherent endotoxin is an important inhibitor of bone formation on orthopaedic implant materials in vitro. This aim will test two complementary hypotheses. The first hypothesis is that removal of adherent endotoxin will increase attachment, proliferation, and/or osteoblastic differentiation of mesenchymal precursor cells cultured on titanium discs. The second hypothesis is that endotoxin hyporesponsiveness will increase attachment, proliferation, and/or osteoblastic differentiation of mesenchymal precursor cells cultured on titanium discs.