Dimer formation of receptor activator of nuclear factor κB induces incomplete osteoclast formation
Dimer formation of receptor activator of nuclear factor κB induces incomplete osteoclast formation
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DOI：
10.1016/j.bbrc.2004.10.024
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发表时间：
2004-12-03
影响因子：
3.1
通讯作者：
Suda, T
中科院分区：
文献类型：
--
作者：
Iwamoto, K;Miyamoto, T;Suda, T
核因子κ B-配体受体激活因子（RANKL）可能通过诱导受体同源三聚体转导适合破骨细胞的分化信号;然而，RANK-三聚体的生物学重要性尚不清楚。为了阐明RANK受体的信号传导机制，我们分析了两种不同类型的同源二聚体诱导剂RANK-TM-FKBP 36 v和hEpoR-RANK-TM对破骨细胞生成的影响。将二聚化组分FKBP 36 v或人促红细胞生成素受体（hEpoR）的胞外部分与缺乏胞外结构域的RANK融合，并分别通过加入二聚化的化学诱导剂AP 20187或促红细胞生成素来诱导该融合蛋白的二聚化。这种处理导致TRAP活性的诱导，TRAP活性是破骨细胞的标志物，呈剂量依赖性，其效率与RANKL诱导的效率相当。然而，与存在RANKL的情况下诱导的破骨细胞相比，二聚化RANK诱导的破骨细胞显示出相对较低水平的多核化、窝形成活性以及降钙素受体和组织蛋白酶K的表达。由于在二聚化RANK诱导的破骨细胞中活化T细胞核因子1（NFATcl）的表达也降低，RANKL引起的RANK寡聚化是通过上调NFATcl产生完全成熟破骨细胞的关键事件。(C)2004年爱思唯尔公司All rights reserved.
Receptor activator of nuclear factor kappaB-ligand (RANKL) transduces a differentiation signal appropriate to osteoclasts likely through induction a receptor homotrimer; however, biological importance of RANK-trimerizarion is unknown. To address the signaling mechanism of the RANK receptor, we analyzed the effect of two different types of homodimer inducers RANK-TM-FKBP36v and hEpoR-RANK-TM on osteoclastogenesis. Dimerizing component FKBP36v or extracellular portion of human erythropoietin receptor (hEpoR) was fused to RANK lacking the extracellular domain, and the dimerization of this fusion protein was induced by addition of the chemical inducer of dimerization AP20187 or erythropoietin, respectively. Such treatment resulted in induction of TRAP-activity, a marker of osteoclast in a dose dependent manner, with an efficiency equivalent to that of induction by RANKL. However, dimcrized-RANK-induced osteoclasts showed relatively low levels of multinucleation, pit forming activity, and expression of calcitonin receptor and cathepsin K, compared with osteoclasts which were induced in the presence of RANKL. As expression of nuclear factor of activated T cells 1 (NFATcl) was also reduced in dimerized-RANK-induced osteoclasts, RANK oligomerization by RANKL is a critical event to generate fully matured osteoclasts through upregulation of NFATcl. (C) 2004 Elsevier Inc. All rights reserved.