Chondroprotective effects of CDK4/6 inhibition via enhanced ubiquitin-dependent degradation of JUN in synovial fibroblasts.
Chondroprotective effects of CDK4/6 inhibition via enhanced ubiquitin-dependent degradation of JUN in synovial fibroblasts.
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通过增强滑膜成纤维细胞中JUN的泛素依赖性降解抑制CDK 4/6的软骨保护作用。
DOI：
10.1093/rheumatology/keab874
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发表时间：
2022-08-03
期刊：
影响因子：
5.5
通讯作者：
Yasuda, Shinsuke
中科院分区：
文献类型：
--
作者：
Hosoya, Tadashi;Saito, Tetsuya;Baba, Hiroyuki;Tanaka, Nao;Noda, Seiji;Komiya, Youji;Tagawa, Yasuhiro;Yamamoto, Akio;Mizoguchi, Fumitaka;Kawahata, Kimito;Miyasaka, Nobuyuki;Kohsaka, Hitoshi;Yasuda, Shinsuke
使用细胞周期蛋白依赖性激酶（CDK）4/6抑制剂（CDKI）靶向滑膜成纤维细胞（SF）可能是通过抑制增殖和MMP-3产生来治疗RA的有效疗法。本研究旨在阐明CDK 4/6抑制对SF软骨保护作用的机制。CDK 4/6活性被CDKI处理抑制或被腺病毒基因转导增强。使用胶原诱导的关节炎模型（CIA）评价软骨保护作用。用定量PCR、ELISA和Western blotting检测基因和蛋白表达。用电泳迁移率变动分析评估核提取物与DNA的结合。进行RNA-Seq以鉴定受CDKI处理影响的基因集。CDKI减弱CIA中的软骨破坏和MMP-3产生。在RASFs中，CDKI损害AP-1组分与DNA的结合，并抑制MMP-1和MMP-3的产生，MMP-1和MMP-3在其启动子中含有AP-1结合序列。CDK 4/6通过抑制泛素化保护JUN免受蛋白酶体依赖性降解。RNA-Seq分析鉴定了CDKI敏感性炎症基因，这些基因与RA相关基因的途径、精氨酸-细胞因子受体相互作用和IL-17信号传导相关。值得注意的是，AP-1基序在这些基因中富集。CDK 4/6抑制的软骨保护作用的机制是通过JUN稳定性受损而减弱AP-1转录活性来实现的。由于CDK 4/6的药理学抑制在癌症治疗中是可耐受的，因此由于其软骨保护和抗炎作用，它也可能对RA患者有益。
Targeting synovial fibroblasts (SF) using a cyclin-dependent kinase (CDK) 4/6 inhibitor (CDKI) could be a potent therapy for RA via inhibition of proliferation and MMP-3 production. This study was designed to elucidate the mechanism of chondroprotective effects on SFs by CDK 4/6 inhibition. CDK4/6 activity was inhibited using CDKI treatment or enhanced by adenoviral gene transduction. Chondroprotective effects were evaluated using a collagen-induced arthritis model (CIA). Gene and protein expression were evaluated with quantitative PCR, ELISA and Western blotting. The binding of nuclear extracts to DNA was assessed with an electrophoresis mobility shift assay. RNA-Seq was performed to identify gene sets affected by CDKI treatment. CDKI attenuated cartilage destruction and MMP-3 production in CIA. In RASFs, CDKI impaired the binding of AP-1 components to DNA and inhibited the production of MMP-1 and MMP-3, which contain the AP-1 binding sequence in their promoter. CDK4/6 protected JUN from proteasome-dependent degradation by inhibiting ubiquitination. The RNA-Seq analysis identified CDKI-sensitive inflammatory genes, which were associated with the pathway of RA-associated genes, cytokine-cytokine receptor interaction and IL-17 signalling. Notably, the AP-1 motif was enriched in these genes. The mechanism of chondroprotective effects by CDK4/6 inhibition was achieved by the attenuation of AP-1 transcriptional activity via the impaired stability of JUN. Because the pharmacologic inhibition of CDK4/6 has been established as tolerable in cancer treatment, it could also be beneficial in patients with RA due to its chondroprotective and anti-inflammatory effects.
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影响因子：
50.3
作者：
Anders L;Ke N;Hydbring P;Choi YJ;Widlund HR;Chick JM;Zhai H;Vidal M;Gygi SP;Braun P;Sicinski P
通讯作者：
Sicinski P
影响因子：
5.2
作者：
Andrikopoulou A;Fiste O;Liontos M;Dimopoulos MA;Zagouri F
通讯作者：
Zagouri F
影响因子：
8
作者：
Lallemand, D;Spyrou, G;Pfarr, CM
通讯作者：
Pfarr, CM
影响因子：
16
作者：
Handschick, Katja;Beuerlein, Knut;Kracht, Michael
通讯作者：
Kracht, Michael
影响因子：
3.7
作者：
Buss H;Handschick K;Jurrmann N;Pekkonen P;Beuerlein K;Müller H;Wait R;Saklatvala J;Ojala PM;Schmitz ML;Naumann M;Kracht M
通讯作者：
Kracht M