Regulatory Mechanisms of Implant-Induced Osteolysis

植入物引起的骨溶解的调节机制

• 批准号: 6725608
• 负责人: YOUSEF ABU-AMER
• 金额: $ 20.88万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6725608
• 关键词: arthroplasty; biological signal transduction; biomaterial compatibility; biomaterial interface interaction; cytokine; implant; laboratory mouse; mitogen activated protein kinase; osteoclasts; pathologic bone resorption; polymethacrylate; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Inflammatory osteolysis induced by implant-derived wear debris is the main cause of total joint replacement failure and remains the major clinical problem in total joint arthroplasty patients. It is accepted that aseptic loosening is associated with infiltration and recruitment of macrophages, neutrophils, lymphocytes, fibroblasts and other cell-types to the implant-bone interface. These processes are associated with abundant secretion of pro-inflammatory cytokines and activation of proteinases that together lead to propagation of the localized inflammatory response and periprosthetic bone erosion. Recent evidence indicates that members of the tumor necrosis factor (TNF) family play a key role in modulating osteolysis. Specifically, TNF and RANKL are known as direct recruiters of osteoclast precursor cells, inducers of differentiation and activation of osteoclasts, the cells responsible for the bone lesion. Previous and current data indicate that polymethylmethacrylate (PMMA) particles may exert their osteoclastic effects directly, indirectly through mediation of pro-inflammatory cytokines, or a combination of both. In this regard, we have documented recently that, in multi-cell type mixed marrow cultures, RANKL (secreted by stromal cells) and TNF-alpha (secreted by osteoclast precursors and stromal cells) activate NFkappaB and, at least in part, mediate PMMA-induced osteoclastogenesis. Equally important, given the important role of MAP kinases in osteoclasts we investigated whether these kinases play a role in PMMA particle-induced osteoclastogenesis and osteolysis. In this regard, we found that PMMA particles directly activate the MAP kinases p38 and Erkl/2 (p42/p44) in osteoclast precursors, and selective inhibition of either kinase reduced osteoclastogenesis. These observations led us to hypothesize that p38 and ERK kinases may play a key role in the development of inflammatory osteolysis. This hypothesis is supported by recent findings indicating that pharmacological inhibition of p38 arrests osteoclast development. Thus our Specific Aims are to, (1) delineate the mechanism(s) by which PMMA particles activate MAP kinase pathways in osteoclast precursors, and (2) inhibit inflammatory osteolysis, in vivo, by blocking PMMA particle-induced p38 and Erkl/2 activation.

描述（由申请人提供）：由植入物衍生的磨损引起的炎症性骨溶解是造成全关节置换失败的主要原因，并且仍然是全关节置换术患者的主要临床问题。人们认为，无菌性松动与巨噬细胞，中性粒细胞，淋巴细胞，成纤维细胞和其他细胞类型的浸润和募集有关。这些过程与促炎性细胞因子的大量分泌以及蛋白酶的激活相关，这共同导致局部炎症反应和虚拟骨侵蚀的传播。最近的证据表明，肿瘤坏死因子（TNF）家族的成员在调节骨溶解中起关键作用。具体而言，TNF和RANKL被称为破骨细胞前体细胞的直接募集，诱导剂分化和破骨细胞激活，是负责骨病变的细胞。以前的和当前的数据表明，聚甲基丙烯酸酯（PMMA）颗粒可以通过促炎细胞因子的介导或两者的组合直接地，间接发挥其破骨肿瘤作用。在这方面，我们最近记录了，在多细胞类型的混合骨髓培养物中，RANKL（由基质细胞分泌）和TNF-Alpha（由破骨细胞前体和基质细胞分泌）激活NFKAPPAB，至少部分介导PMMA诱导的骨诱导的骨塑料。同样重要的是，鉴于MAP激酶在破骨细胞中的重要作用，我们研究了这些激酶是否在PMMA颗粒诱导的骨构成和骨溶解中起作用。在这方面，我们发现PMMA颗粒在破骨细胞前体中直接激活MAP激酶p38和ERKL/2（P42/P44），并选择性抑制两种激酶减少了骨质质质量发生。这些观察结果使我们假设p38和ERK激酶可能在炎症骨溶解的发展中起关键作用。最近的发现证明了这一假设，表明p38抑制破骨细胞的发育。因此，我们的具体目的是（1）描述PMMA颗粒在破骨细胞前体中激活MAP激酶途径的机制，以及（2）通过阻断PMMA粒度诱导的P38和ERKL/2激活来阻断体内，体内，体内抑制炎症性骨化。