MECHANISMS OF IMPLANT PARTICLE-INDUCED OSTEOCLASTOGENESI

植入颗粒诱导破骨细胞的机制

• 批准号: 6534507
• 负责人: JOHN C CLOHISY
• 金额: $ 7.7万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6534507
• 关键词: biomaterial compatibility; biomaterial interface interaction; genetic transcription; inflammation; joint prosthesis; laboratory mouse; medical implant science; nuclear factor kappa beta; osteoclasts; particle; pathologic bone resorption; phosphorylation; polymethacrylate; protein tyrosine kinase; tumor necrosis factor alpha

DESCRIPTION (Taken from the application): Total joint replacement implant survival is limited by aseptic loosening of the prosthesis. Implant loosening results from periprosthetic bone resorption which is mediated by a chronic inflammatory response to implant-derived particulate debris. Understanding the basic cellular and molecular events involved in this osteolytic process will introduce potential molecular targets for therapeutic intervention. Previous experiments with genetic blockade of the TNF signaling pathway, prevents experimental, particle-induced osteolysis. Thus, we focus on the nuclear transcription factor kappa B (NF-kB) which is essential for osteoclast formation and is a known mediator of TNF-induced gene transcription. We show in osteoclast precursor cells, that implant particles induce TNF expression and are potent activators of NF-kB. TNF activates NF-kB in these cells via a novel, cell-specific mechanism involving the tyrosine kinase c-src and the NF-kB inhibitory protein (IkB). This suggests that particles may exert their effect via a similar signaling pathway. We hypothesize that in osteoclast precursor cells polymethylmethacrylate (PMMA) particles activate NF-kB via a TNF signaling pathway involving c-src phosphorylation of IkB and that blocking particle-induced NF-kB activation will inhibit osteoclastogenesis in vitro. Our aims are: 1) to determine the mechanism(s) by which PMMA particles induce NF-kB activation in osteoclast precursor cells and 2) to determine the effect of blocking NF-kB activation on PMMA-induced osteoclastogenesis in vitro.

描述（摘自应用程序）： 全关节置换植入物的存活受到无菌性松动的限制 假肢。假体周围骨吸收导致种植体松动 由对植入物衍生颗粒的慢性炎症反应介导 碎片。了解其中涉及的基本细胞和分子事件 溶骨过程将引入潜在的治疗分子靶点 干涉。 之前对 TNF 信号通路进行基因阻断的实验， 防止实验性颗粒诱导的骨溶解。因此，我们重点关注 破骨细胞必需的核转录因子 kappa B (NF-kB) 形成并且是 TNF 诱导基因转录的已知介质。我们展示在 破骨细胞前体细胞，植入颗粒诱导 TNF 表达并 是 NF-kB 的有效激活剂。 TNF 通过一种新型的、 涉及酪氨酸激酶 c-src 和 NF-kB 的细胞特异性机制 抑制蛋白（IkB）。这表明粒子可能发挥其作用 通过类似的信号通路。我们假设在破骨细胞前体中 细胞聚甲基丙烯酸甲酯 (PMMA) 颗粒通过 TNF 激活 NF-kB 涉及 IkB 的 c-src 磷酸化和阻断的信号通路 颗粒诱导的 NF-kB 激活将在体外抑制破骨细胞生成。我们的 目的是：1) 确定 PMMA 颗粒诱导 NF-kB 的机制 破骨细胞前体细胞的激活和2)确定的效果 体外阻断 NF-kB 激活 PMMA 诱导的破骨细胞生成。