STING promotes senescence, apoptosis, and extracellular matrix degradation in osteoarthritis via the NF-κB signaling pathway.
STING promotes senescence, apoptosis, and extracellular matrix degradation in osteoarthritis via the NF-κB signaling pathway.
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STING 通过 NF-κB 信号通路促进骨关节炎的衰老、细胞凋亡和细胞外基质降解
DOI：
10.1038/s41419-020-03341-9
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发表时间：
2021-01-04
影响因子：
9
通讯作者：
Zhang X
中科院分区：
文献类型：
--
作者：
Guo Q;Chen X;Chen J;Zheng G;Xie C;Wu H;Miao Z;Lin Y;Wang X;Gao W;Zheng X;Pan Z;Zhou Y;Wu Y;Zhang X
脱氧核糖核酸(DNA)损伤是骨关节炎(OA)的主要病理因素，但DNA损伤导致骨关节炎的机制尚不清楚。以往的研究表明，干扰素基因刺激因子环状GMP-AMP合成酶(CGAS)参与了DNA损伤反应。因此，本研究旨在探讨cGAS-STING信号级联中的主要效应因子--STING在体外和体内的骨性关节炎进展中的作用。在这项研究中，我们研究了STING在人和小鼠骨性关节炎组织中的表达，以及在白介素1β(IL-1β)作用下的软骨细胞中的表达。在STING过表达和击倒软骨细胞中，研究了STING对细胞外基质(ECM)代谢、细胞凋亡和衰老的影响。此外，还探讨了NF-κB信号转导通路及其在细胞外基质代谢、细胞凋亡和衰老调节中的作用。关节腔内注射刺痛敲除慢病毒以评价其对小鼠在体骨关节炎的治疗作用。结果表明，IL-1β对人和小鼠骨性关节炎组织及软骨细胞中STING的表达均有明显的上调作用。过表达的STING促进了基质金属蛋白酶13和ADAMTS5的表达，抑制了聚集素和II型胶原的表达，并促进了暴露于和未经IL-1β处理的软骨细胞的凋亡和衰老。机制研究表明，STING激活了NF-κB信号通路，而阻断NF-κB信号可减轻STING诱导的细胞凋亡和衰老，改善STING诱导的细胞外基质代谢失衡。在活体研究中，已经证明，刺击下减轻了内侧半月板诱导的小鼠骨性关节炎发展的不稳定性。综上所述，STING通过激活核因子-κB信号通路促进骨性关节炎的发生，而抑制STING可能为骨性关节炎的治疗提供了一条新的途径。
Damaged deoxyribonucleic acid (DNA) is a primary pathologic factor for osteoarthritis (OA); however, the mechanism by which DNA damage drives OA is unclear. Previous research demonstrated that the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) participates in DNA damage response. As a result, the current study aimed at exploring the role STING, which is the major effector in the cGAS-STING signaling casacde, in OA progress in vitro, as well as in vivo. In this study, the expression of STING was evaluated in the human and mouse OA tissues, and in chondrocytes exposed to interleukin-1 beta (IL-1β). The influences of STING on the metabolism of the extracellular matrix (ECM), apoptosis, and senescence, were assessed in STING overexpressing and knocking-down chondrocytes. Moreover, the NF-κB-signaling casacde and its role in the regulatory effects of STING on ECM metabolism, apoptosis, and senescence were explored. The STING knockdown lentivirus was intra-articularly injected to evaluate its therapeutic impact on OA in mice in vivo. The results showed that the expression of STING was remarkably elevated in the human and mouse OA tissues and in chondrocytes exposed to IL-1β. Overexpression of STING promoted the expression of MMP13, as well as ADAMTS5, but suppressed the expression of Aggrecan, as well as Collagen II; it also enhanced apoptosis and senescence in chondrocytes exposed to and those untreated with IL-1β. The mechanistic study showed that STING activated NF-κB signaling cascade, whereas the blockage of NF-κB signaling attenuated STING-induced apoptosis and senescence, and ameliorated STING-induced ECM metabolism imbalance. In in vivo study, it was demonstrated that STING knockdown alleviated destabilization of the medial meniscus-induced OA development in mice. In conclusion, STING promotes OA by activating the NF-κB signaling cascade, whereas suppression of STING may provide a novel approach for OA therapy.
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影响因子：
7
作者：
Kim, J.;Xu, M.;Grishko, V.
通讯作者：
Grishko, V.
影响因子：
7.7
作者：
El Mai, Mounir;Marzullo, Marta;Ferreira, Miguel Godinho
通讯作者：
Ferreira, Miguel Godinho
影响因子：
21.3
作者：
Glück S;Guey B;Gulen MF;Wolter K;Kang TW;Schmacke NA;Bridgeman A;Rehwinkel J;Zender L;Ablasser A
通讯作者：
Ablasser A
影响因子：
7
作者：
Lewis, J. S.;Hembree, W. C.;Furman, B. D.;Tippets, L.;Cattel, D.;Huebner, J. L.;Little, D.;DeFrate, L. E.;Kraus, V. B.;Guilak, F.;Olson, S. A.
通讯作者：
Olson, S. A.
影响因子：
64.8
作者：
Dou Z;Ghosh K;Vizioli MG;Zhu J;Sen P;Wangensteen KJ;Simithy J;Lan Y;Lin Y;Zhou Z;Capell BC;Xu C;Xu M;Kieckhaefer JE;Jiang T;Shoshkes-Carmel M;Tanim KMAA;Barber GN;Seykora JT;Millar SE;Kaestner KH;Garcia BA;Adams PD;Berger SL
通讯作者：
Berger SL