CELLULAR MECHANISMS OF IMPLANT LOOSENING

关节植入物的无菌松动是临床骨科的主要问题之一。我们和其他人最近提供的证据表明，粘附内毒素参与了磨损颗粒对细胞因子产生和破骨细胞分化的刺激。然而，内毒素在体内的重要性研究较少。因此，我们提出的研究旨在更确切地验证附着内毒素是磨损颗粒诱导的骨溶解的重要刺激物这一总体假设。这一假设并不表明附着性内毒素是骨溶解的唯一刺激物，只是内毒素是一个重要的刺激物。提出了以下具体目标：目标1。目的：探讨内毒素的体外作用机制。这一目标将测试三种可供选择但并非相互排斥的假设。第一种假设是磨损颗粒将内毒素传递给应答细胞。第二个假设是，附着在磨损颗粒上的内毒素增加了对反应细胞的附着和/或吞噬作用。第三种假设是，粘附的内毒素改变了细胞对磨损颗粒的反应性质。目标2。目的：探讨体内黏附内毒素是否为颗粒性骨溶解的重要刺激物。这一目的将有两个相互补充的假设：第一个假设是，粘附内毒素是磨损颗粒诱导的小鼠骨溶解的重要刺激物。第二个假设是从无菌性松动患者身上提取的磨损颗粒含有大量的粘附内毒素。目标3。目的：探讨黏附内毒素是否为体外骨科植入材料骨形成的重要抑制剂。这一目标将检验两个互补的假设。第一种假设是去除附着内毒素会增加钛盘上培养的间充质前体细胞的附着、增殖和/或成骨分化。第二个假设是内毒素低反应性会增加钛盘上培养的间充质前体细胞的附着、增殖和/或成骨分化。

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.