14-3-3 epsilon is an intracellular component of TNFR2 receptor complex and its activation protects against osteoarthritis.
14-3-3 epsilon is an intracellular component of TNFR2 receptor complex and its activation protects against osteoarthritis.
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DOI：
10.1136/annrheumdis-2021-220000
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发表时间：
2021-12
影响因子：
27.4
通讯作者：
Liu CJ
中科院分区：
文献类型：
--
作者：
Fu W;Hettinghouse A;Chen Y;Hu W;Ding X;Chen M;Ding Y;Mundra J;Song W;Liu R;Yi YS;Attur M;Samuels J;Strauss E;Leucht P;Schwarzkopf R;Liu CJ
骨关节炎（OA）是最常见的关节疾病;然而，OA发展机制的不确定性限制了治疗靶点的进展。TNF信号转导与OA的发病机制有关。TNFR 1主要介导炎症，而新的证据表明TNFR 2在几种疾病和病症中起抗炎和保护作用。本研究旨在破译软骨细胞和OA中的TNFR 2信号。通过生化共纯化和蛋白质组学筛选，分离TNFR 2复合物的胞内辅因子。采用批量和单细胞RNA-seq来确定14-3-3 ε（14-3-3ε）在人正常和OA软骨中的表达。使用转录因子活性筛选来分离TNFR 2/14-3-3ε下游的转录因子。进行了各种基于细胞的测定和具有天然存在的和免疫诱导的OA的基因修饰小鼠，以检查该途径在软骨细胞和OA中的重要性。信号分子14-3-3ε被鉴定为软骨细胞中TNFR 2复合物的细胞内组分，其响应于颗粒蛋白前体（PGRN），所述颗粒蛋白前体是已知主要通过激活TNFR 2来防止OA的生长因子。14-3-3ε在OA中表达下调，其缺乏可加重OA。14-3-3ε是PGRN调节软骨细胞代谢所必需的。此外，14-3-3ε的整体和软骨细胞特异性缺失在很大程度上消除了PGRN对OA的治疗作用。此外，PGRN/TNFR 2/14-3-3ε通过激活ERK依赖性Elk-1而抑制软骨细胞中的NF-κB来传递信号。本研究将14-3-3ε鉴定为软骨细胞中TNFR 2受体复合物响应PGRN的诱导组分，并提出了OA发病机制中先前未被认识的TNFR 2途径。
Osteoarthritis (OA) is the most common joint disease; however, the indeterminate nature of mechanisms by which OA develops has restrained advancement of therapeutic targets. TNF signaling has been implicated in the pathogenesis of OA. TNFR1 primarily mediates inflammation, whereas emerging evidences demonstrate that TNFR2 plays an anti-inflammatory and protective role in several diseases and conditions. This study aims to decipher TNFR2 signaling in chondrocytes and OA. Biochemical co-purification and proteomics screen were performed to isolate the intracellular co-factors of TNFR2 complex. Bulk and single cell RNA-seq were employed to determine 14-3-3 epsilon (14-3-3ε) expression in human normal and OA cartilage. Transcription factor activity screen was used to isolate the transcription factors downstream of TNFR2/14-3-3ε. Various cell-based assays and genetically-modified mice with naturally-occurring and surgically-induced OA were performed to examine the importance of this pathway in chondrocytes and OA. Signaling molecule 14-3-3ε was identified as an intracellular component of TNFR2 complexes in chondrocytes in response to progranulin (PGRN), a growth factor known to protect against OA primarily through activating TNFR2. 14-3-3ε was downregulated in OA and its deficiency deteriorated OA. 14-3-3ε was required for PGRN regulation of chondrocyte metabolism. In addition, both global and chondrocyte-specific deletion of 14-3-3ε largely abolished PGRN’s therapeutic effects against OA. Furthermore, PGRN/TNFR2/14-3-3ε signaled through activating ERK dependent Elk-1 while suppressing NF-κB in chondrocytes. This study identifies 14-3-3ε as an inducible component of TNFR2 receptor complex in response to PGRN in chondrocytes and presents a previously-unrecognized TNFR2 pathway in the pathogenesis of OA.
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影响因子：
7
作者：
Lai, Y.;Yu, X-P.;Zhang, Y.;Tian, Q.;Song, H.;Mucignat, M. T.;Perris, R.;Samuels, J.;Krasnokutsky, S.;Attur, M.;Greenberg, J. D.;Abramson, S. B.;Di Cesare, P. E.;Liu, C. J.
通讯作者：
Liu, C. J.
影响因子：
12.7
作者：
Chen D;Shen J;Zhao W;Wang T;Han L;Hamilton JL;Im HJ
通讯作者：
Im HJ
DOI：
10.1073/pnas.1605195113
发表时间：
2016-10-25
影响因子：
11.1
作者：
Dong, Yun;Fischer, Roman;Eisel, Ulrich L. M.
通讯作者：
Eisel, Ulrich L. M.
影响因子：
4.8
作者：
Fu, Wenyu;Hu, Wenhuo;Liu, Chuan-ju
通讯作者：
Liu, Chuan-ju
影响因子：
4.8
作者：
Kishore, N;Sommers, C;Tripp, CS
通讯作者：
Tripp, CS