CCN2 enhances RANKL-induced osteoclast differentiation via direct binding to RANK and OPG
CCN2 enhances RANKL-induced osteoclast differentiation via direct binding to RANK and OPG
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DOI：
10.1016/j.bone.2014.12.058
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发表时间：
2015-04-01
期刊：
影响因子：
4.1
通讯作者：
Takigawa, Masaharu
中科院分区：
文献类型：
--
作者：
Aoyama, Eriko;Kubota, Satoshi;Takigawa, Masaharu
CCN家族蛋白2/结缔组织生长因子(CCN2/CTGF)是一种对软骨细胞、成骨细胞、破骨细胞和内皮细胞等间充质细胞具有多潜能的因子。CCN2也被认为是其他细胞因子和受体的调节器，通过与它们直接的分子相互作用。我们筛选了与CCN2结合的其他因子，发现核因子-kappaB受体激活物(RANK)是其中之一。RANK又称肿瘤坏死因子相关激活诱导细胞因子(TRANCE)受体，其信号转导通路在破骨细胞发生中起关键作用。表面等离子体共振(SPR)分析证实了CCN2与RANK具有显著的亲和力。事实上，在破骨前RAW264.7细胞中，CCN2增强了RANK介导的信号转导，如发生在NF-kappa B、p38和JNK通路中；而CCN2对RANKL结合没有影响。此外，CCN2还与RANKL的诱骗受体骨保护素(OPG)显著结合。值得注意的是，OPG显著抑制CCN2与RANK的结合，CCN2可取消OPG对破骨细胞分化的抑制作用。这些发现表明，CCN2是RANK/RANKL/OPG成骨系统中的第四个候选因子，该系统通过直接相互作用来调节OPG和RANK。(C)2014 Elsevier Inc.保留所有权利。
CCN family protein 2/connective tissue growth factor (CCN2/CTGF) is a multi-potent factor for mesenchymal cells such as chondrocytes, osteoblasts, osteoclasts, and endothelial cells. CCN2 is also known as a modulator of other cytokines and receptors via direct molecular interactions with them. We screened additional factors binding to CCN2 and found receptor activator of NF-kappa B (RANK) as one of them. RANK is also known as TNF-related activation-induced cytokine (TRANCE) receptor, and its signaling plays a critical role in osteoclastogenesis. Notable affinity between CCN2 and RANK was confirmed by using surface plasmon resonance (SPR) analysis. In fact, CCN2 enhanced the RANK-mediated signaling, such as occurs in NF-kappa B, p38 and JNK pathways, in pre-osteoclastic RAW264.7 cells; whereas CCN2 had no influence on RANK RANK ligand (RANKL) binding. Moreover, CCN2 also significantly bound to osteoprotegerin (OPG), which is a decoy receptor of RANKL. Of note, OPG markedly inhibited the binding between CCN2 and RANK; and CCN2 canceled the inhibitory effect of OPG on osteoclast differentiation. These findings suggest CCN2 as a candidate of the fourth factor in the RANK/RANKL/OPG system for osteodastogenesis, which regulates OPG and RANK via direct interaction. (C) 2014 Elsevier Inc. All rights reserved.