MECHANISMS OF IMPLANT PARTICLE-INDUCED OSTEOCLASTOGENESI

描述（取自应用程序）： 全关节置换植入物的生存受到关节囊无菌性松动的限制。 假肢假体周围骨吸收导致植入物松动， 是由对植入物衍生颗粒的慢性炎症反应介导的 碎片了解这一过程中涉及的基本细胞和分子事件 溶骨过程将引入潜在的分子靶点， 干预 先前的TNF信号通路基因阻断实验， 防止实验性颗粒诱导的骨质溶解。因此，我们重点关注 核转录因子κ B（NF-κ B）是破骨细胞所必需的 形成，并且是TNF诱导的基因转录的已知介质。我们进去 破骨细胞前体细胞，植入颗粒诱导TNF表达， 是NF-κ B的有效激活剂。TNF通过一种新的， 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磷酸化的信号通路和阻断 颗粒诱导的NF-κ B活化将抑制体外破骨细胞生成。我们 目的是：1）确定PMMA颗粒诱导NF-κ B的机制 破骨细胞前体细胞中的活化和2）确定 在体外阻断NF-kB对PMMA诱导的破骨细胞生成的活化。

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.