WEAR DEBRIS OSTEOLYSIS--NEW STRATEGIES FOR PREVENTION

描述（改编自研究者摘要）：假体周围 关节置换术周围骨质溶解导致假体松动 这是我国人口老龄化面临的主要问题之一。 它 已知位于假体周围膜中的单核细胞 全关节置换术分泌刺激骨吸收的细胞因子 并导致植入失败。 特别是肿瘤坏死因子α 肿瘤坏死因子-α（TNF-α）和白细胞介素-6（IL-6）与骨质溶解有关。 这发生在松动的植入物周围。 尽管在临床上 虽然这个问题的相关性，很少有人知道的基本机制， 细胞因子释放对磨损碎屑的响应。 申请人建议 研究这些基本机制的基本原理是， 这个过程中涉及的原则将表明可能的治疗方法， 接近。 人单核细胞系THP-1已经部分地 表征和初步工作表明，该细胞系是理想的 微粒碎片对单核细胞影响的研究。 这些 细胞产生细胞因子的基础水平非常低，对 用钛刺激，细胞因子产生大量增加， mRNA水平，并且容易被外源DNA转染。 在这 建议，表征THP-1对钛的反应将是 完成建立这些细胞作为第一个人类细胞系， 假体松动机制的研究。 启动子构建体 将TNF-α和IL-6转染到THP-1细胞中，以确定TNF-α和IL-6的表达。 细胞因子的顺式调节区和反式激活因子 通过磨损碎屑释放。 初步结果表明，细胞因子 在钛刺激的单核细胞中的释放受药理学调节， 改变细胞内信号传导途径的药物以及细胞因子 IL-4和IL-10。 这些药物对细胞因子释放和细胞因子分泌的影响 将测定启动子活性。 由于其中一些代理商，包括 磷酸二酯酶抑制剂环丙沙星 可能的临床意义，这些不同的药物的潜力， 抑制骨吸收将在1）中进行研究。 假体周围 膜器官培养; 2）体外骨吸收模型。 这些 这些研究可能会为更完整的 了解松动过程，阐明为什么有些人 放松和其他人没有，并导致可能的治疗方法。

DESCRIPTION (Adapted from the investigator's Abstract): Periprosthetic osteolysis surrounding joint arthroplasties leads to prosthetic loosening and failure and is one of the major issues facing our aging population. It is known that monocytes located in the periprosthetic membrane surrounding total joint arthroplasties secrete cytokines which stimulate bone resorption and lead to implant failure. In particular, tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) have been implicated in the osteolysis which occurs around loose implants. Despite the magnitude and clinical relevance of this problem, little is known about the basic mechanisms of cytokine release in response to wear debris. The applicant proposes to investigate these basic mechanisms with the rationale that understanding of the principles involved in this process will suggest possible therapeutic approaches. The human monocytic cell line, THP-1, has been partially characterized and preliminary work suggests that this cell line is ideal for the investigation of the effects of particulate debris on monocytes. These cells have very low basal levels of cytokine production, respond to stimulation with titanium with large increases in cytokine production and mRNA levels, and are readily transfected with foreign DNA. In this proposal, the characterization of THP-1 responses to titanium will be completed establishing these cells as the first human cell line for investigation of the mechanism of prosthetic loosening. Promoter constructs for TNF-alpha and IL-6 will be transfected into THP-1 cells to determine the cis-acting regulatory regions and trans-activating factors involved cytokine release by wear debris. Preliminary results have demonstrated that cytokine release in titanium-stimulated monocytes is regulated by pharmacological agents which alter intracellular signaling pathways as well as by cytokines IL-4 and IL-10. The effects of these agents on cytokine release and promoter activity will be determined. Since some of these agents, including the phosphodiesterase inhibitor ciprofloxacin and pentoxifylline have possible clinical significance, the potential of these various agents to inhibit bone resorption will be investigated in 1). a periprosthetic membrane organ cultures; and 2) in in vitro bone resorption models. These studies will potentially lay the groundwork for a more complete understanding of the loosening process, shed light on why some individuals loosen and others do not, and lead to possible therapeutic approaches.