A RANK/TRAF6-dependent signal transduction pathway is essential for osteoclast cytoskeletal organization and resorptive function
A RANK/TRAF6-dependent signal transduction pathway is essential for osteoclast cytoskeletal organization and resorptive function
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DOI：
10.1074/jbc.m202009200
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发表时间：
2002-11-15
影响因子：
4.8
通讯作者：
Dougall, WC
中科院分区：
文献类型：
--
作者：
Armstrong, AP;Tometsko, ME;Dougall, WC
通过核因子κ b受体激活因子（RANK）的信号传导对破骨细胞的分化和激活至关重要，破骨细胞主要负责骨吸收。遗传上缺乏RANK或同源RANK配体的动物由于缺乏骨吸收和重塑而严重骨质疏松。在配体结合和受体寡聚化后，RANK通过募集细胞内肿瘤坏死因子受体相关因子（TRAFs）来激发生化信号。为了了解破骨细胞发生中RANK介导的信号转导机制，我们设计了一个系统，通过将RANK cDNA转移到遗传上缺乏RANK的造血前体中，来概括体外破骨细胞的分化和激活。选择性不能结合不同TRAF蛋白的RANK构建体的基因转移表明，RANK下游影响破骨细胞分化的TRAF通路在功能上是冗余的。相反，RANK与TRAF6的相互作用对于细胞骨架结构的正常形成和破骨细胞的功能吸收活性是绝对必要的。此外，通过同样利用TRAF6的白细胞介素-1受体发出的信号，可以挽救在没有RANK/TRAF6相互作用时观察到的破骨细胞激活缺陷。这些研究首次定义了RANK细胞质尾部控制破骨细胞特异性分化和激活途径的功能域。
Signaling through receptor activator of nuclear factor-kappaB (RANK) is essential for the differentiation and activation of osteoclasts, the cell principally responsible for bone resorption. Animals genetically deficient in RANK or the cognate RANK ligand are profoundly osteopetrotic because of the lack of bone resorption and remodeling. RANK provokes biochemical signaling via the recruitment of intracellular tumor necrosis factor receptor-associated factors (TRAFs) after ligand binding and receptor oligomerization. To understand the RANK-mediated signal transduction mechanism in osteoclastogenesis, we have designed a system to recapitulate osteoclast differentiation and activation in vitro by transfer of the RANK cDNA into hematopoietic precursors genetically deficient in RANK. Gene transfer of RANK constructs that are selectively incapable of binding different TRAF proteins revealed that TRAF pathways downstream of RANK that affect osteoclast differentiation are functionally redundant. In contrast, the interaction of RANK with TRAF6 is absolutely required for the proper formation of cytoskeletal structures and functional resorptive activity of osteoclasts. Moreover, signaling via the interleukin-1 receptor, which also utilizes TRAF6, rescues the osteoclast activation defects observed in the absence of RANK/TRAF6 interactions. These studies are the first to define the functional domains of the RANK cytoplasmic tail that control specific differentiation and activation pathways in osteoclasts.