Clohisy John C, Frazier Elfaridah, Hirayama Teruhisa, Abu-Amer Yousef
Department of Orthopaedic Surgery, Barnes-Jewish Hospital at Washington University, School of Medicine, One Barnes-Jewish Hospital Plaza, 11300 West Pavilion, Campus Box 8233, St. Louis, Missouri 63110, USA.
J Orthop Res. 2003 Mar;21(2):202-12. doi: 10.1016/S0736-0266(02)00133-X.
RANKL is a TNF superfamily member and an essential cytokine mediator of developmental osteoclastogenesis. We examined the role of RANKL in PMMA particle-induced osteoclastogenesis in vitro. In murine whole bone marrow cultures, PMMA particles stimulate a 2.5 fold increase in secreted RANKL, a 5-8 fold increase in osteoclast number and induce the formation of giant multinuclear osteoclasts. RANKL and TNF, potential cytokine mediators of PMMA, had similar osteoclastogenic effects. The RANKL inhibitor OPG was utilized to define the role of RANKL in mediating the PMMA response and was found to inhibit basal and PMMA particle-induced osteoclastogenesis. Additionally, particles stimulate osteoclast formation in RANKL-primed osteoclast precursor cells (devoid of supporting stromal cells) while RANKL untreated osteoclast precursors demonstrate no osteoclastogenic response to particles. Since TNF can potentiate RANKL action and is thought to mediate implant osteolysis we analyzed TNF(-/-) whole bone marrow cultures to elucidate the role of this cytokine. In TNF(-/-) cultures basal osteoclastogenesis remains intact, yet the PMMA effect is blunted. Finally, we show that PMMA, RANKL and TNF all activate the NF-kB and c-jun/AP-1 signaling pathways which are both fundamental to osteoclast formation and are potential sites of signal convergence in RANKL-mediated particle osteoclastogenesis.
RANKL是肿瘤坏死因子超家族成员，也是发育性破骨细胞生成过程中一种重要的细胞因子介质。我们在体外研究了RANKL在聚甲基丙烯酸甲酯（PMMA）颗粒诱导破骨细胞生成中的作用。在小鼠全骨髓培养中，PMMA颗粒刺激分泌型RANKL增加2.5倍，破骨细胞数量增加5 - 8倍，并诱导形成巨大的多核破骨细胞。RANKL和TNF作为PMMA潜在的细胞因子介质，具有相似的破骨细胞生成作用。利用RANKL抑制剂骨保护素（OPG）来确定RANKL在介导PMMA反应中的作用，发现其可抑制基础状态和PMMA颗粒诱导的破骨细胞生成。此外，颗粒在经RANKL预处理的破骨细胞前体细胞（缺乏支持性基质细胞）中刺激破骨细胞形成，而未经RANKL处理的破骨细胞前体对颗粒无破骨细胞生成反应。由于TNF可增强RANKL的作用，并被认为介导植入物骨溶解，我们分析了TNF基因敲除小鼠的全骨髓培养，以阐明这种细胞因子的作用。在TNF基因敲除小鼠的培养中，基础破骨细胞生成保持完整，但PMMA的作用减弱。最后，我们表明PMMA、RANKL和TNF均激活NF-κB和c-jun/AP-1信号通路，这两条通路对于破骨细胞形成均至关重要，并且是RANKL介导的颗粒性破骨细胞生成中潜在的信号汇聚位点。
