Inflammatory Cytokines Stabilize SOXC Transcription Factors to Mediate the Transformation of Fibroblast-Like Synoviocytes in Arthritic Disease.
Inflammatory Cytokines Stabilize SOXC Transcription Factors to Mediate the Transformation of Fibroblast-Like Synoviocytes in Arthritic Disease.
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DOI：
10.1002/art.40386
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发表时间：
2018-03
期刊：
影响因子：
--
通讯作者：
Lefebvre V
中科院分区：
文献类型：
--
作者：
Bhattaram P;Muschler G;Wixler V;Lefebvre V
成纤维细胞样滑膜细胞（FLS）产生关键的滑液和组织成分，以确保健康条件下的关节完整性，而它们变成癌症样并积极促进炎性关节炎中的关节退行性变。本研究的目的是确定SOXC转录因子SOX 4和SOX 11在正常和炎症条件下是否有助于FLS活动，SOXC转录因子SOX 4和SOX 11在关节发育和许多癌症类型中起关键作用。我们灭活了成年小鼠FLS中的SOXC基因，并研究了其对关节稳态和肿瘤坏死因子（TNF）诱导的关节炎的影响。我们使用关节炎患者的原代细胞和滑膜活检标本来分析炎症信号和SOXC蛋白之间的相互作用。出生后SOXC基因的失活对其他健康小鼠的关节完整性没有重大影响。然而，它阻碍了表达人TNF的转基因小鼠的滑膜增生和关节变性。这些作用通过SOX 4/11通过增加FLS的存活和迁移来放大TNF对FLS的致病性影响的能力来解释。SOXC RNA水平不受TNF和其他促炎细胞因子的影响，但SOXC蛋白强烈稳定，并能够增强TNF诱导的FLS转化相关基因的上调。证实了这些发现在人类疾病中的相关性，SOXC蛋白水平，而不是RNA水平，在关节炎患者的炎症滑膜中显著高于非炎症滑膜。SOXC蛋白是关节炎疾病中FLS转化过程中促炎细胞因子的靶点和关键介质。因此，靶向这些蛋白质可以改善目前治疗关节炎疾病和其他炎症性疾病的策略。
Fibroblast‐like synoviocytes (FLS) produce key synovial fluid and tissue components to ensure joint integrity under healthy conditions, whereas they become cancer‐like and aggressively contribute to joint degeneration in inflammatory arthritis. The aim of this study was to determine whether the SOXC transcription factors SOX4 and SOX11, whose functions are critical in joint development and many cancer types, contribute to FLS activities under normal and inflammatory conditions. We inactivated the SOXC genes in FLS from adult mice and studied the effect on joint homeostasis and tumor necrosis factor (TNF)–induced arthritis. We used primary cells and synovial biopsy specimens from arthritis patients to analyze the interactions between inflammatory signals and SOXC proteins. Postnatal inactivation of the SOXC genes had no major effect on joint integrity in otherwise healthy mice. However, it hampered synovial hyperplasia and joint degeneration in transgenic mice expressing human TNF. These effects were explained by the ability of SOX4/11 to amplify the pathogenic impact of TNF on FLS by increasing their survival and migration. SOXC RNA levels were not changed by TNF and other proinflammatory cytokines, but SOXC proteins were strongly stabilized and able to potentiate the TNF‐induced up‐regulation of genes involved in FLS transformation. Substantiating the relevance of these findings in human disease, SOXC protein levels, but not RNA levels, were significantly higher in inflamed synovium than in noninflamed synovium from arthritis patients. SOXC proteins are targets and pivotal mediators of proinflammatory cytokines during FLS transformation in arthritic diseases. Targeting of these proteins could thus improve current strategies to treat arthritic diseases and possibly other inflammatory diseases.
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DOI：
10.1083/jcb.201405098
发表时间：
2014-12-08
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bhattaram P;Penzo-Méndez A;Kato K;Bandyopadhyay K;Gadi A;Taketo MM;Lefebvre V
通讯作者：
Lefebvre V
影响因子：
6
作者：
Lauzier, Annie;Lavoie, Roxane R.;Dubois, Claire M.
通讯作者：
Dubois, Claire M.
SOX18 转录因子的小分子抑制剂
影响因子：
8.6
作者：
Fontaine, Frank;Overman, Jeroen;Francois, Mathias
通讯作者：
Francois, Mathias
影响因子：
56.9
作者：
Lee, David M.;Kiener, Hans P.;Brenner, Michael B.
通讯作者：
Brenner, Michael B.
影响因子：
13.3
作者：
Ntougkos, Evangelos;Chouvardas, Panagiotis;Kollias, George
通讯作者：
Kollias, George