Mitogen-activated protein (MAP) kinases mediate PMMA-induction of osteoclasts
Mitogen-activated protein (MAP) kinases mediate PMMA-induction of osteoclasts
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DOI：
10.1016/s0736-0266(03)00081-0
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发表时间：
2003-11-01
影响因子：
2.8
通讯作者：
Abu-Amer, Y
中科院分区：
文献类型：
--
作者：
Abbas, S;Clohisy, JC;Abu-Amer, Y
种植体磨屑引起的炎性骨溶解与多种细胞类型在种植体-骨界面上的渗透有关，导致大量的促炎细胞因子的分泌和蛋白水解酶的激活，共同导致局部炎症反应的传播和假体周围的骨侵蚀。肿瘤坏死因子家族成员被认为是炎症和骨溶解的直接介质。这些细胞因子通过激活转录因子NF-kappaB和某些MAP激酶，包括c-jun、erks和p38，发挥其破骨作用，这些都是已知的对破骨细胞发育至关重要的。我们最近发现，破骨细胞因子肿瘤坏死因子和RANKL在炎性骨溶解的发生发展中起着关键作用。我们还发现，PMMA颗粒至少部分地通过诱导RANKL、TNF和激活转录因子NF-kappaB来刺激破骨细胞的形成。更重要的是，我们的数据表明，破骨细胞生成因子的抑制剂、肿瘤坏死因子和RANKL可以抑制颗粒诱导的破骨细胞生成。在目前的研究中，我们研究了PMMA颗粒是否激活了MAP激酶，以及这些激酶作为骨溶解介质的潜在作用。在破骨细胞前体细胞中，我们发现PMMA颗粒能够显著而快速地激活p38和ERK的MAPK。这种激活是特异的，通过用特定的抑制化合物完全阻断而明显。类似地，我们发现PMMA颗粒激活JNK通路，该通路已知参与炎症和破骨细胞形成事件。我们还发现p38MAPK调节PMMA激活的核因子-kappaB，从而为破骨细胞前体中颗粒的作用提供了可能的机制。最后，我们提供了MAP激酶的特定抑制剂能够抑制PMMA刺激的破骨细胞生成的证据。这些数据提供了证据，证明MAP激酶是颗粒诱导的破骨细胞形成的有效中介。(C)2003年骨科研究会。爱思唯尔有限公司出版。保留所有权利。
Inflammatory osteolysis induced by implant-derived wear debris is associated with infiltration of various cell-types to the implant-bone interface leading to abundant secretion of pro-inflammatory cytokines and activation of proteinases that together lead to propagation of the localized inflammatory response and periprosthetic bone erosion. Tumor necrosis factor family members are considered to be direct mediators of inflammation and osteolysis. These cytokines exert their osteoclastic effects via activation of the transcription factor NF-kappaB and certain MAP kinases, including c-Jun, Erks and p38, all known to be essential for the development of osteoclasts. We have recently documented that the osteoclastogenic cytokines TNF and RANKL play a pivotal role in the development of inflammatory osteolysis. We have also found that PMMA particles stimulate osteoclastogenesis, at least in part, by induction of RANKL, TNF, and by activation of the transcription factor NF-kappaB. More importantly, our data indicate that inhibitors of the osteoclastogenic factors, TNF and RANKL abrogate particle-induced osteoclastogenesis. In the current study, we investigated if PMMA particles activate MAP kinases, and the potential role of these kinases as mediators of osteolysis. Using kinase assays, we show that in osteoclast precursors, PMMA particles markedly and rapidly activate p38 and ERK MAP kinases. This activation was specific, evident by complete blockade with specific inhibitory compounds. Similarly, we show that PMMA particles activate the JNK pathway, which is known to be involved in inflammatory and osteoclastogenic events. We also show that p38 MAP kinase regulates PMMA-activation of NF-kappaB, thus providing a possible mechanism for particle action in osteoclast precursors. Finally, we provide evidence that specific inhibitors of MAP kinases are capable of inhibiting PMMA-stimulated osteoclastogenesis. These data provide evidence that MAP kinases are potent mediators of particle-induced osteoclastogenesis. (C) 2003 Orthopaedic Research Society. Published by Elsevier Ltd. All rights reserved.