RANKL downregulates cell surface CXCR6 expression through JAK2/STAT3 signaling pathway during osteoclastogenesis
RANKL downregulates cell surface CXCR6 expression through JAK2/STAT3 signaling pathway during osteoclastogenesis
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破骨细胞生成过程中RANKL通过JAK2/STAT3信号通路下调细胞表面CXCR6表达
DOI：
10.1016/j.bbrc.2012.10.122
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发表时间：
2012-12-14
影响因子：
3.1
通讯作者：
Liu, Xiangyuan
中科院分区：
文献类型：
--
作者：
Li, Changhong;Zhao, Jinxia;Liu, Xiangyuan
核因子-kappaB受体激活剂配体(RANKL)作为肿瘤坏死因子家族的一员，在破骨细胞的分化和功能中起着至关重要的作用。近年来，趋化因子及其受体在破骨细胞生成中发挥重要作用，但CXCL16-CXCR6是否参与RANKL介导的破骨细胞生成尚不清楚。在本研究中，我们首次报道了RANKL以剂量依赖的方式降低CXCR6，这可能是通过抑制CXCL16诱导的Akt和STAT3信号通路。有趣的是，RANKL介导的CXCR6还原可能与通过磷酸化激活STAT3有关。当JAK2/STAT3抑制剂AG490阻断STAT3的激活时，RANKL不能阻断破骨细胞形成过程中CXCR6的表达。然而，单独使用CXCL16并不能增强RANKL介导的破骨细胞分化，也不能改变RANKL受体RANK mRNA的表达。这些结果表明，CXCL16-CXCR6的减少在RANKL介导的破骨细胞形成中起关键作用，这主要是通过激活JAK2/STAT3信号来实现的。CXCL16-CXCR6轴可能成为类风湿性关节炎、骨质疏松症等骨吸收疾病治疗干预的新靶点。(C)2012 Elsevier Inc.保留所有权利。
The receptor activator of nuclear factor-kappa B ligand (RANKL), as a member of the tumor necrosis factor (TNF) family, plays an essential role in osteoclast differentiation and function. Chemokines and their receptors have recently been shown to play critical roles in osteoclastogenesis, however, whether CXCL16-CXCR6 plays role in RANKL-mediated osteoclastogenesis is unknown. In this study, we first reported that RANKL decreased CXCR6 in a dose-dependent manner, which may be through deactivation of Akt and STAT3 signaling induced by CXCL16. Interestingly, RANKL-mediated CXCR6 reduction may be associated to the activation of STAT3 by phosphorylation. When STAT3 activation was blocked by JAK2/STAT3 inhibitor AG490, RANKL failed to shut down CXCR6 expression during osteoclastogenesis. However, CXCL16 alone did not augment RANKL-mediated osteoclast differentiation and did not alter RANKL-receptor RANK mRNA expression. These results demonstrate that reduction of CXCL16-CXCR6 is critical in RANKL-mediated osteoclastogenesis, which is mainly through the activation of JAK2/STAT3 signaling. CXCL16-CXCR6 axis may become a novel target for the therapeutic intervention of bone resorbing diseases such as rheumatoid arthritis and osteoporosis. (C) 2012 Elsevier Inc. All rights reserved.