Ets-2 Propagates IL-6 Trans-Signaling Mediated Osteoclast-Like Changes in Human Rheumatoid Arthritis Synovial Fibroblast.
Ets-2 Propagates IL-6 Trans-Signaling Mediated Osteoclast-Like Changes in Human Rheumatoid Arthritis Synovial Fibroblast.
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DOI：
10.3389/fimmu.2021.746503
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发表时间：
2021
影响因子：
7.3
通讯作者：
Ahmed S
中科院分区：
文献类型：
--
作者：
Singh AK;Haque M;Madarampalli B;Shi Y;Wildman BJ;Basit A;Khuder SA;Prasad B;Hassan Q;Ouseph MM;Ahmed S
风湿性关节炎滑膜成纤维细胞（RASFs）通过产生多效细胞因子白细胞介素-6（IL-6）而促进滑膜炎症和骨破坏。然而，IL-6推动RASFs促进骨丢失的分子机制尚未完全了解。在本研究中，我们研究了IL-6和IL-6受体（IL-6/IL-6 R）诱导的人RASFs反式信号转导的作用。IL-6反式信号转导导致RASFs中抗酒石酸酸性磷酸酶（TRAP）阳性染色显著增加，体外成骨表面的小凹形成增加约3倍。IL-6/IL-6 R引起转录因子Ets 2的表达和核转位呈剂量依赖性增加，这与破骨细胞特异性标志蛋白RANKL、组织蛋白酶B（CTSB）和组织蛋白酶K（CTSK）在RASF中的表达相关。CTSB和CTSK启动子的染色质免疫沉淀（ChIP）分析显示，IL-6/IL-6 R刺激后，Ets 2直接结合和转录激活。Ets 2的敲低显著抑制RASF中IL-6/IL-6 R诱导的RANKL、CTSB和CTSK表达和TRAP染色，并抑制RASF侵袭表型的标志物，如Thy 1和podoplanin（PDPN）。对分泌组的质谱分析鉴定了RASF独特地响应IL-6/IL-6 R产生的113种蛋白质，这些蛋白质在生物信息学上预测了其对朝向破骨细胞样表型的代谢重编程的影响。这些发现确定了Ets 2在IL-6反式信号诱导RASF分子重编程为破骨细胞样细胞中的作用，并可能导致RASF异质性。
Rheumatoid arthritis synovial fibroblasts (RASFs) contribute to synovial inflammation and bone destruction by producing a pleiotropic cytokine interleukin-6 (IL-6). However, the molecular mechanisms through which IL-6 propels RASFs to contribute to bone loss are not fully understood. In the present study, we investigated the effect of IL-6 and IL-6 receptor (IL-6/IL-6R)-induced trans-signaling in human RASFs. IL-6 trans-signaling caused a significant increase in tartrate-resistant acid phosphatase (TRAP)-positive staining in RASFs and enhanced pit formation by ~3-fold in the osteogenic surface in vitro. IL-6/IL-6R caused dose-dependent increase in expression and nuclear translocation of transcription factor Ets2, which correlated with the expression of osteoclast-specific signature proteins RANKL, cathepsin B (CTSB), and cathepsin K (CTSK) in RASFs. Chromatin immunoprecipitation (ChIP) analysis of CTSB and CTSK promoters showed direct Ets2 binding and transcriptional activation upon IL-6/IL-6R stimulation. Knockdown of Ets2 significantly inhibited IL-6/IL-6R-induced RANKL, CTSB, and CTSK expression and TRAP staining in RASFs and suppressed markers of RASF invasive phenotype such as Thy1 and podoplanin (PDPN). Mass spectrometry analysis of the secretome identified 113 proteins produced by RASFs uniquely in response to IL-6/IL-6R that bioinformatically predicted its impact on metabolic reprogramming towards an osteoclast-like phenotype. These findings identified the role of Ets2 in IL-6 trans-signaling induced molecular reprogramming of RASFs to osteoclast-like cells and may contribute to RASF heterogeneity.
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DOI：
10.1002/art.40504
发表时间：
2018-07
期刊：
Arthritis & rheumatology (Hoboken, N.J.)
影响因子：
--
作者：
Falconer J;Murphy AN;Young SP;Clark AR;Tiziani S;Guma M;Buckley CD
通讯作者：
Buckley CD
影响因子：
--
作者：
Kasperkovitz, PV;Timmer, TCG;Verweij, CL
通讯作者：
Verweij, CL
影响因子：
4.8
作者：
Franchimont, N;Rydziel, S;Canalis, E
通讯作者：
Canalis, E
DOI：
10.4161/jkst.25763
发表时间：
2013-10-01
期刊：
JAK-STAT
影响因子：
--
作者：
Kojima H;Inoue T;Kunimoto H;Nakajima K
通讯作者：
Nakajima K
影响因子：
4.8
作者：
Kapasa ER;Giannoudis PV;Jia X;Hatton PV;Yang XB
通讯作者：
Yang XB