Current Understanding of RANK Signaling in Osteoclast Differentiation and Maturation.
Current Understanding of RANK Signaling in Osteoclast Differentiation and Maturation.
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DOI：
10.14348/molcells.2017.0225
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发表时间：
2017-10
影响因子：
3.8
通讯作者：
Lee SY
中科院分区：
文献类型：
--
作者：
Park JH;Lee NK;Lee SY
破骨细胞是来源于造血前体细胞的骨吸收细胞，其存活、增殖、分化和活化需要巨噬细胞集落刺激因子和核因子-κB配体受体激活因子（RANKL）。RANKL与其受体RANK的结合触发破骨细胞前体分化为破骨细胞。该过程依赖于RANKL-RANK信号传导，其在时间上由各种衔接蛋白和激酶调节。在这里，我们总结了目前的理解机制，调节RANK信号在破骨细胞生成。在早期阶段，RANK信号传导通过募集衔接分子（如肿瘤坏死因子受体相关因子6（TRAF 6））介导，导致丝裂原活化蛋白激酶（MAPK）和转录因子核因子-κB（NF-κB）和激活蛋白-1（AP-1）活化。活化的NF-κB诱导活化的T细胞胞质核因子1（NFATc 1），其是关键的破骨细胞生成调节剂。在信号传导的中间阶段，共刺激信号通过活化的磷脂酶Cγ2（PLCγ2）与c-Fos/AP-1一起诱导Ca 2+振荡，其中Ca 2+信号传导促进NFATc 1的稳健产生。在破骨细胞生成的晚期阶段，NFATc 1易位到细胞核中，在那里它诱导许多负责细胞融合和功能的破骨细胞特异性靶基因。
Osteoclasts are bone-resorbing cells that are derived from hematopoietic precursor cells and require macrophage-colony stimulating factor and receptor activator of nuclear factor-κB ligand (RANKL) for their survival, proliferation, differentiation, and activation. The binding of RANKL to its receptor RANK triggers osteoclast precursors to differentiate into osteoclasts. This process depends on RANKL-RANK signaling, which is temporally regulated by various adaptor proteins and kinases. Here we summarize the current understanding of the mechanisms that regulate RANK signaling during osteoclastogenesis. In the early stage, RANK signaling is mediated by recruiting adaptor molecules such as tumor necrosis factor receptor-associated factor 6 (TRAF6), which leads to the activation of mitogen-activated protein kinases (MAPKs), and the transcription factors nuclear factor-κB (NF-κB) and activator protein-1 (AP-1). Activated NF-κB induces the nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), which is the key osteoclastogenesis regulator. In the intermediate stage of signaling, the co-stimulatory signal induces Ca2+ oscillation via activated phospholipase Cγ2 (PLCγ2) together with c-Fos/AP-1, wherein Ca2+ signaling facilitates the robust production of NFATc1. In the late stage of osteoclastogenesis, NFATc1 translocates into the nucleus where it induces numerous osteoclast-specific target genes that are responsible for cell fusion and function.