Regulatory Mechanisms of Implant-Induced Osteolysis

描述(申请人提供)：植入物产生的磨屑引起的炎性骨溶解是关节置换完全失败的主要原因，也是全关节置换术患者的主要临床问题。无菌性松动与种植体骨界面巨噬细胞、中性粒细胞、淋巴细胞、成纤维细胞和其他细胞类型的渗透和募集有关。这些过程与促炎细胞因子的大量分泌和蛋白水解酶的激活有关，共同导致局部炎症反应的传播和假体周围的骨侵蚀。最近的证据表明，肿瘤坏死因子家族的成员在调节骨溶解中起着关键作用。具体地说，肿瘤坏死因子和RANKL被认为是破骨细胞前体细胞的直接募集者，是破骨细胞分化和激活的诱导者，而破骨细胞是导致骨损伤的细胞。以往和目前的数据表明，聚甲基丙烯酸甲酯(PMMA)颗粒可能直接、间接地通过促炎细胞因子或两者的组合发挥其破骨作用。在这方面，我们最近证实，在多细胞类型的混合骨髓培养中，RANKL(由基质细胞分泌)和TNF-α(由破骨细胞前体和基质细胞分泌)激活NFkappaB，并至少部分地介导PMMA诱导的破骨细胞的形成。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颗粒诱导的破骨细胞形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细胞中的MAP激酶p38和Erkl/2(p42/p44)，选择性地抑制这两种激酶中的任何一种都会减少破骨细胞的形成。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。这一假设得到了最近研究结果的支持，这些发现表明，药物抑制p38可以阻止破骨细胞的发育。因此，我们的具体目标是：(1)阐明PMMA颗粒激活破骨细胞前体细胞中的MAP激酶通路的机制(S)，以及(2)通过阻断PMMA颗粒诱导的p38和Erk1/2的激活，在体内抑制炎性骨溶解。

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.