RelB is the NF-κB subunit downstream of NIK responsible for osteoclast differentiation
RelB is the NF-κB subunit downstream of NIK responsible for osteoclast differentiation
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DOI：
10.1073/pnas.0708576105
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发表时间：
2008-03-11
影响因子：
11.1
通讯作者：
Novack, Deborah Veis
中科院分区：
文献类型：
--
作者：
Vaira, Sergio;Johnson, Trevor;Novack, Deborah Veis
核因子-kappaB诱导激酶(NIK)是破骨细胞发生所必需的，它的缺失导致P100胞浆滞留导致替代的和经典的核因子-kappaB功能受阻。我们现在发现，P100的缺失恢复了NIK缺乏的破骨细胞(OC)前体分化和正常化RelB和P65信号的能力。RelB的过度表达也恢复了Nik-/-前体细胞的分化，但不是p65。此外，RelB-/-前体在培养中不能形成OCs，这种缺陷可以通过重新表达RelB来修复，但不能通过过表达p65来修复。为了进一步支持RelB在OCS中的作用，我们在活体内用肿瘤坏死因子-α挑战RelB-/-小鼠，发现破骨细胞反应减弱。然后，我们通过使用B16黑色素瘤模型，在RelB-/-和Nik-/-小鼠中检测了肿瘤诱导的骨溶解。肿瘤细胞在骨髓中的生长与WT对照组相似，但缺乏RelB或墨水完全阻止了肿瘤诱导的骨小梁丢失。因此，替代的NF-kappa B途径，最终激活RelB，在OCs的分化中具有关键和特定的作用，这是p65无法弥补的。
NF-kappa B inducing kinase (NIK) is required for osteoclastogenesis in response to pathologic stimuli, and its loss leads to functional blockade of both alternative and classical NF-kappa B caused by cytoplasmic retention by p100. We now show that deletion of p100 restores the capacity of NIK-deficient osteoclast (OC) precursors to differentiate and normalizes RelB and p65 signaling. Differentiation of NIK-/- precursors is also restored by overexpression of RelB, but not p65. Additionally, RelB-/- precursors fail to form OCs in culture, and this defect is rescued by re-expression of RelB, but not by overexpression of p65. To further support the role of RelB in OCs, we challenged RelB-/- mice with TNF-alpha in vivo and found a diminished osteoclastogenic response. We then examined tumor-induced osteolysis in both RelB-/- and NIK-/- mice by using the B16 melanoma model. Growth of tumor cells in the bone marrow was similar to WT controls, but the absence of either RelB or INK completely blocked the tumor-induced loss of trabecular bone. Thus, the alternative NF-kappa B pathway, culminating in activation of RelB, has a key and specific role in the differentiation of OCs that cannot be compensated for by p65.