Curcumin (diferuloylmethane) inhibits receptor activator of NF-kB ligand-induced NF-kB activation in osteoclast precursors and suppresses osteoclastogenesis
Curcumin (diferuloylmethane) inhibits receptor activator of NF-kB ligand-induced NF-kB activation in osteoclast precursors and suppresses osteoclastogenesis
复制标题
DOI：
10.4049/jimmunol.172.10.5940
复制
发表时间：
2004-05-15
影响因子：
4.4
通讯作者：
Aggarwal, BB
中科院分区：
文献类型：
--
作者：
Bharti, AC;Takada, Y;Aggarwal, BB
大量研究表明，炎性细胞因子在破骨细胞生成中起主要作用，导致骨吸收，这通常与癌症和其他疾病有关。基因缺失研究表明，NF-κ B配体受体激活因子（RANKL）是破骨细胞生成的关键介质之一。RANKL如何介导破骨细胞生成尚不完全清楚，但抑制RANKL信号传导的药物具有抑制破骨细胞生成的潜力。在这份报告中，我们研究了姜黄素（二阿魏酰甲烷），一种来自姜黄的色素，在RAW 264.7细胞（一种小鼠单核细胞系）中抑制RANKL信号传导和破骨细胞生成的能力。用RANKL处理这些细胞激活NF-κ B，并将细胞预暴露于姜黄素完全抑制RANKL诱导的NF-κ B激活。姜黄素抑制IkappaB α激酶活化和IkappaB α磷酸化至IkappaB α降解的途径。RANKL在这些单核细胞中诱导破骨细胞生成，姜黄素抑制RANKL和TNF诱导的破骨细胞生成和窝形成。姜黄素与RANKL一起加入时，对破骨细胞生成的抑制作用最大，RANKL后2天加入时，抑制作用最小。姜黄素是否通过抑制NF-κ B抑制RANKL诱导的破骨细胞生成也得到了独立证实，因为RANKL未能激活用显性阴性形式的IkappaB α稳定转染的细胞中的NF-κ B，同时未能诱导破骨细胞生成。因此，总体而言，这些结果表明RANKL通过激活NF-κ B诱导破骨细胞生成，姜黄素处理抑制NF-κ B激活和RANKL诱导的破骨细胞生成。
Numerous studies have indicated that inflammatory cytokines play a major role in osteoclastogenesis, leading to the bone resorption that is frequently associated with cancers and other diseases. Gene deletion studies have shown that receptor activator of NF-kappaB ligand (RANKL) is one of the critical mediators of osteoclastogenesis. How RANKL mediates osteoclastogenesis is not fully understood, but an agent that suppresses RANKL signaling has potential to inhibit osteoclastogenesis. In this report, we examine the ability of curcumin (diferuloylmethane), a pigment derived from turmeric, to suppress RANKL signaling and osteoclastogenesis in RAW 264.7 cells, a murine monocytic cell line. Treatment of these cells with RANKL activated NF-kappaB, and preexposure of the cells to curcumin completely suppressed RANKL-induced NF-kappaB activation. Curcumin inhibited the pathway leading from activation of IkappaBalpha kinase and IkappaBalpha phosphorylation to IkappaBalpha degradation. RANKL induced osteoclastogenesis in these monocytic cells, and curcumin inhibited both RANKL- and TNF-induced osteoclastogenesis and pit formation. Curcumin suppressed osteoclastogenesis maximally when added together with RANKL and minimally when it was added 2 days after RANKL. Whether curcumin inhibits RANKL-induced osteoclastogenesis through suppression of NF-kappaB was also confirmed independently, as RANKL failed to activate NF-kappaB in cells stably transfected with a dominant-negative form of IkappaBalpha and concurrently failed to induce osteoclastogenesis. Thus overall these results indicate that RANKL induces osteoclastogenesis through the activation of NF-kappaB, and treatment with curcumin inhibits both the NF-kappaB activation and osteoclastogenesis induced by RANKL.