MECHANISMS OF IMPLANT PARTICLE-INDUCED OSTEOCLASTOGENESI

描述(取自申请表)： 关节置换术的无菌松动限制了全关节置换术的存活率 假肢。假体松动是由假体周围骨吸收引起的 是由对植入物来源的微粒的慢性炎症反应所介导的 碎片。了解与此相关的基本细胞和分子事件 骨溶解过程将引入潜在的治疗分子靶点 干预。 之前关于基因阻断肿瘤坏死因子信号通路的实验， 防止实验性的颗粒诱导的骨溶解。因此，我们关注的是 破骨细胞必需的核转录因子-kB 形成，是已知的肿瘤坏死因子诱导基因转录的中介物。我们展示在 破骨细胞前体细胞，植入颗粒诱导肿瘤坏死因子表达和 是核因子-kB的有效激活剂。肿瘤坏死因子通过一种新型的、 涉及酪氨酸激酶c-src和核因子-kB的细胞特异性机制 抑制蛋白(IKB)。这表明粒子可以发挥它们的作用。 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)颗粒通过肿瘤坏死因子激活核因子-kB 参与IKB c-src磷酸化的信号通路及其阻断 颗粒诱导的核因子-kB的激活在体外会抑制破骨细胞的形成。我们的 目的是：1)确定PMMA颗粒诱导核因子-kB的机制(S) 破骨细胞前体细胞的激活和2)确定 阻断核因子-kB在PMMA诱导破骨细胞生成中的作用。

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.