Dominant-negative IκB facilitates apoptosis of osteoclasts by tumor necrosis factor-α
Dominant-negative IκB facilitates apoptosis of osteoclasts by tumor necrosis factor-α
复制标题
DOI：
10.1074/jbc.m208619200
复制
发表时间：
2003-05-30
影响因子：
4.8
通讯作者：
Abu-Amer, Y
中科院分区：
文献类型：
--
作者：
Abbas, S;Abu-Amer, Y
破骨细胞是唯一的骨吸收细胞。这些细胞在病理条件下的活性增强导致骨丢失疾病的发展，例如骨质溶解、骨质疏松症和类风湿性关节炎。我们以前已经表明，肿瘤坏死因子α（TNF）强烈诱导破骨细胞前体的破骨细胞生成，并通过激活转录因子NF-κ B来实现。最重要的是，最近的研究表明，NF-κ B是破骨细胞发育所必需的。这种转录因子也被证明是炎症性疾病（包括与骨相关的疾病）的重要介质。在这方面，我们已经表明，各种突变形式的IkappaB α是破骨细胞生成的有效抑制剂。在这项研究中，我们检查了在TNF存在的情况下DN-IkappaB对成熟破骨细胞和前破骨细胞发育的直接影响。我们的研究结果表明，一旦致力于破骨细胞的途径，前破骨细胞形成巨大的和过度活跃的破骨细胞响应TNF。然而，在TNF暴露之前向培养物施用DN-IkappaB避免了TNF的破骨细胞生成作用进入细胞凋亡。筛选DN-IkappaB和TNF诱导的细胞凋亡的潜在介质显示，caspase 3、caspase 9、聚（ADP-核糖）聚合酶和Bax被激活，而Bcl-X-L、cIAP-1和TRAF 6的水平降低。总之，这些发现表明，在NF-κ B失活的条件下，促存活因子的水平降低，这反过来又促进了TNF诱导促凋亡因子，导致细胞凋亡。
Osteoclasts are the sole bone-resorbing cells. Heightened activity of these cells under pathological conditions leads to the development of bone loss diseases, such as osteolysis, osteoporosis, and rheumatoid arthritis. We have shown previously that tumor necrosis factor alpha-(TNF) strongly induces osteoclastogenesis of preosteoclasts and do so through activation of the transcription factor, NF-kappaB. Most importantly, recent studies have shown that NF-kappaB is required for the development of osteoclasts. This transcription factor has also been proven as an essential mediator of inflammatory diseases including those related to bone. In this regard, we have shown that various mutated forms of IkappaBalpha are potent inhibitors of osteoclastogenesis. In this study, we examined the direct effect of DN-IkappaB on mature and preosteoclast development in the presence of TNF. Our findings indicate that once committed to the osteoclastogenic pathway, preosteoclasts form giant and hyperactive osteoclasts in response to TNF. However, administration of DN-IkappaB to cultures prior to TNF exposure averts the osteoclastogenic effect of TNF into apoptosis. Screening potential mediators of DN-IkappaB and TNF-induced apoptosis shows that caspase 3, caspase 9, poly(ADP-ribose) polymerase, and Bax are activated, whereas levels of Bcl-X-L, cIAP-1, and TRAF6 were reduced. Taken together, these findings suggest that under conditions of NF-kappaB inactivity levels of pro-survival factors are diminished, which in turn facilitates TNF induction of pro-apoptotic factors leading to apoptosis.