Reciprocal inhibition of YAP/TAZ and NF-κB regulates osteoarthritic cartilage degradation.
Reciprocal inhibition of YAP/TAZ and NF-κB regulates osteoarthritic cartilage degradation.
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YAP/TAZ 和 NF-κB 的相互抑制调节骨关节炎软骨退化
DOI：
10.1038/s41467-018-07022-2
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发表时间：
2018-11-01
影响因子：
16.6
通讯作者：
Mak KK
中科院分区：
文献类型：
--
作者：
Deng Y;Lu J;Li W;Wu A;Zhang X;Tong W;Ho KK;Qin L;Song H;Mak KK
骨关节炎是由于关节软骨损伤导致的老年人群疼痛和残疾的主要原因之一。这保证了对可以保护软骨免于退化和降解的信号传导机制的研究。在这里，我们表明，在实验性骨关节炎，雅普激活转基因过表达或删除其上游抑制激酶Mst 1/2保留关节软骨的完整性，而软骨细胞中的雅普删除促进软骨破坏的小鼠模型。我们的工作表明，雅普是必要的和足够的维持软骨稳态骨关节炎。在机制上，炎性细胞因子，如TNFα或IL-1β，通过TAK 1介导的磷酸化触发雅普/TAZ降解。此外，雅普直接与TAK 1相互作用，并通过抑制TAK 1的底物可及性来减弱NF-κB信号传导。我们的研究建立了Hippo-YAP/TAZ和NF-κB信号在骨关节炎发病机制中调节基质降解酶表达和软骨降解的相互拮抗作用。
Osteoarthritis is one of the leading causes of pain and disability in the aged population due to articular cartilage damage. This warrants investigation of signaling mechanisms that could protect cartilage from degeneration and degradation. Here we show in a murine model of experimental osteoarthritis that YAP activation by transgenic overexpression or by deletion of its upstream inhibitory kinases Mst1/2 preserves articular cartilage integrity, whereas deletion of YAP in chondrocytes promotes cartilage disruption. Our work shows that YAP is both necessary and sufficient for the maintenance of cartilage homeostasis in osteoarthritis. Mechanistically, inflammatory cytokines, such as TNFα or IL-1β, trigger YAP/TAZ degradation through TAK1-mediated phosphorylation. Furthermore, YAP directly interacts with TAK1 and attenuates NF-κB signaling by inhibiting substrate accessibility of TAK1. Our study establishes a reciprocal antagonism between Hippo-YAP/TAZ and NF-κB signaling in regulating the induction of matrix-degrading enzyme expression and cartilage degradation during osteoarthritis pathogenesis.
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影响因子：
4.6
作者：
Iqbal SM;Leonard C;Regmi SC;De Rantere D;Tailor P;Ren G;Ishida H;Hsu C;Abubacker S;Pang DS;Salo PT;Vogel HJ;Hart DA;Waterhouse CC;Jay GD;Schmidt TA;Krawetz RJ
通讯作者：
Krawetz RJ
影响因子：
14.9
作者：
Deutsch EW;Csordas A;Sun Z;Jarnuczak A;Perez-Riverol Y;Ternent T;Campbell DS;Bernal-Llinares M;Okuda S;Kawano S;Moritz RL;Carver JJ;Wang M;Ishihama Y;Bandeira N;Hermjakob H;Vizcaíno JA
通讯作者：
Vizcaíno JA
影响因子：
13.3
作者：
Ismail, Heba M.;Yamamoto, Kazuhiro;Saklatvala, Jeremy
通讯作者：
Saklatvala, Jeremy
影响因子：
6
作者：
Pfander, D;Swoboda, B;Kirsch, T
通讯作者：
Kirsch, T
影响因子：
2.1
作者：
Pacifici, Maurizio;Koyama, Eiki;Iwamoto, Masahiro
通讯作者：
Iwamoto, Masahiro