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（申请人提供）：由植入物产生的磨损碎片引起的炎性骨溶解是全关节置换术失败的主要原因，并且仍然是全关节置换术患者的主要临床问题。人们普遍认为，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向植入物-骨界面的浸润和募集有关。这些过程与促炎细胞因子的大量分泌和蛋白酶的激活有关，共同导致局部炎症反应和假体周围骨侵蚀的传播。最近的证据表明肿瘤坏死因子 (TNF) 家族的成员在调节骨质溶解方面发挥着关键作用。具体而言，TNF 和 RANKL 被认为是破骨细胞前体细胞的直接募集剂、破骨细胞分化和活化的诱导剂，破骨细胞是造成骨损伤的细胞。先前和当前的数据表明，聚甲基丙烯酸甲酯（PMMA）颗粒可能直接、通过促炎细胞因子的介导间接发挥其破骨作用，或两者的组合。在这方面，我们最近记录到，在多细胞类型混合骨髓培养物中，RANKL（由基质细胞分泌）和TNF-α（由破骨细胞前体细胞和基质细胞分泌）激活NFkappaB，并至少部分介导PMMA -诱导破骨细胞生成。同样重要的是，考虑到 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 颗粒诱导的破骨细胞生成和骨溶解中发挥作用。在这方面，我们发现PMMA颗粒直接激活破骨细胞前体中的MAP激酶p38和Erk1/2 (p42/p44)，并且选择性抑制任一激酶减少破骨细胞生成。这些观察结果使我们推测 p38 和 ERK 激酶可能在炎症性骨溶解的发展中发挥关键作用。最近的研究结果表明 p38 的药理抑制可阻止破骨细胞的发育，这一假设得到了支持。因此，我们的具体目标是，(1) 阐明 PMMA 颗粒激活破骨细胞前体中 MAP 激酶途径的机制，以及 (2) 通过阻断 PMMA 颗粒诱导的 p38 和 Erkl/2 来抑制体内炎症性骨质溶解激活。