The Pivotal Role of the Alternative NF-κB Pathway in Maintenance of Basal Bone Homeostasis and Osteoclastogenesis
The Pivotal Role of the Alternative NF-κB Pathway in Maintenance of Basal Bone Homeostasis and Osteoclastogenesis
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DOI：
10.1359/jbmr.091030
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发表时间：
2010-04-01
影响因子：
6.2
通讯作者：
Aoki, Kazuhiro
中科院分区：
文献类型：
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作者：
Soysa, Niroshani S.;Alles, Neil;Aoki, Kazuhiro
替代NF-κ B途径主要由NF-κ B诱导激酶（NIK）、I kappa B激酶α组成（IKK α）、p100/p52和RelB替代性NF-κ B信号传导的标志是通过NIK将p100加工成p52，从而允许p52和RelB结合。然而，骨生物学中替代性NF-κ B激活的生理相关性，为了阐明替代途径在骨稳态中的作用，我们首先分析了具有缺陷的NIK并且不能处理p100，导致p52缺失的淋巴瘤形成（aly/aly）小鼠。我们观察到骨矿物质密度（BMD）和骨体积增加，表明骨硬化表型这些小鼠在体外和体内的RANKL诱导的破骨细胞生成中也具有显著缺陷。NF-κ B DNA结合测定显示RelA，RelB，RANKL刺激后aly/aly破骨细胞核提取物中p50和p52无结合活性为了确定p100本身的作用而不受p52伴随缺乏的影响，我们使用p100（-/-）小鼠，其特异性缺乏p100抑制剂但仍表达p52.p100（-/-）小鼠由于破骨细胞增加和成骨细胞数量减少而具有骨质减少表型，这是通过删除relB基因的一个等位基因而挽救的。与野生型（WT）对照相比，由于破骨细胞活性降低而成骨细胞数量增加，骨量显著增加，揭示了RelB在骨形成中迄今未知的作用。我们的数据表明，替代NF-κ B B途径，特别是p100的抑制作用，在基础和刺激的破骨细胞生成中起关键作用，以及RelB在骨形成和骨吸收中的重要性。2010年美国骨与矿物质研究学会
The alternative NF-kappa B pathway consists predominantly of NF-kappa B-inducing kinase (NIK), I kappa B kinase alpha (IKK alpha), p100/p52, and RelB The hallmark of the alternative NF-kappa B signaling is the processing of p100 into p52 through NIK, thus allowing the binding of p52 and RelB The physiologic relevance of alternative NF-kappa B activation in bone biology, however, is not well understood To elucidate the role of the alternative pathway in bone homeostasis, we first analyzed alymphoplasic (aly/aly) mice, which have a defective NIK and are unable to process p100, resulting in the absence of p52 We observed increased bone mineral density (BMD) and bone volume, indicating an osteopetrotic phenotype These mice also have a significant defect in RANKL-induced osteoclastogenesis in vitro and in vivo NF-kappa B DNA-binding assays revealed reduced activity of RelA, RelB, and p50 and no binding activity of p52 in aly/aly osteoclast nuclear extracts after RANKL stimulation To determine the role of p100 itself without the influence of a concomitant lack of p52, we used p100(-/-) mice, which specifically lack the p100 inhibitor but still express p52.p100(-/-) mice have an osteopenic phenotype owing to the increased osteoclast and decreased osteoblast numbers that was rescued by the deletion of one allele of the relB gene Deletion of both allele of relB resulted in a significantly increased bone mass owing to decreased osteoclast activity and increased osteoblast numbers compared with wildtype (WT) controls, revealing a hitherto unknown role for RelB in bone formation Our data suggest a pivotal role of the alternative NF-kappa B pathway, especially of the inhibitory role of p100, in both basal and stimulated osteoclastogenesis and the importance of RelB in both bone formation and resorption. 2010 American Society for Bone and Mineral Research