Modulation of IL-6 induced RANKL expression in arthritic synovium by a transcription factor SOX5.
Modulation of IL-6 induced RANKL expression in arthritic synovium by a transcription factor SOX5.
复制标题
转录因子 SOX5 调节关节炎滑膜中 IL-6 诱导的 RANKL 表达
DOI：
10.1038/srep32001
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发表时间：
2016-08-23
影响因子：
4.6
通讯作者：
Tan W
中科院分区：
文献类型：
--
作者：
Feng X;Shi Y;Xu L;Peng Q;Wang F;Wang X;Sun W;Lu Y;Tsao BP;Zhang M;Tan W
核因子κB受体激活因子配体（RANKL）在类风湿关节炎（RA）骨侵蚀中起重要作用。我们先前报道了较年轻的RA发病年龄与RANKL启动子SNP之间的相关性，RANKL启动子SNP通过与转录因子SOX 5结合来提高启动子活性。在这里，我们研究了RA滑膜成纤维细胞（SF）中与RANKL表达相关的SOX 5水平的调节以及胶原诱导的关节炎（CIA）小鼠骨侵蚀的发展。我们的数据表明，与骨关节炎患者相比，RA患者的滑膜和滑液中SOX 5水平较高。促炎细胞因子上调SOX 5和RANKL的表达，在原发性RA SF和类风湿性滑膜成纤维细胞系，MH 7A。在MH 7A细胞中，SOX 5的过表达导致RANKL水平显著增加，而SOX 5的敲低导致IL-6介导的RANKL上调减少。染色质免疫沉淀（ChIP）显示，与未处理的细胞相比，IL-6处理的MH 7A细胞中抗SOX 5免疫沉淀物中RANKL特异性DNA的富集约为3倍。局部沉默SOX 5基因显著减少CIA小鼠RANKL阳性细胞和骨质侵蚀。这些发现表明SOX 5是RA SF中IL-6诱导的RANKL表达的重要调节因子。
Receptor activator of nuclear factor κB ligand (RANKL) is critically involved in bone erosion of rheumatoid arthritis (RA). We previously reported association between younger age at onset of RA and a RANKL promoter SNP that conferred an elevated promoter activity via binding to a transcription factor SOX5. Here we study the regulation of SOX5 levels in relation to RANKL expression in RA synovial fibroblasts (SF) and the development of bone erosion in the collagen-induced arthritis (CIA) mouse. Our data indicated SOX5 levels were higher in synovium and synovial fluid from RA compared to osteoarthritis patients. Pro-inflammatory cytokines upregulated SOX5 and RANKL expression in both primary RA SF and the rheumatoid synovial fibroblast cell line, MH7A. Overexpression of SOX5 resulted in significantly increased RANKL levels, while knockdown of SOX5 resulted in diminished IL-6 mediated RANKL upregulation in MH7A cells. Chromatin immunoprecipitation (ChIP) showed approximately 3-fold enrichment of RANKL-specific DNA in anti-SOX5 immunoprecipitate in IL-6 treated MH7A cells as compared to untreated cells. Locally silencing SOX5 gene significantly diminished RANKL positive cells and bone erosion in CIA mice. These findings suggest SOX5 is an important regulator of IL-6-induced RANKL expression in RA SF.