Obeticholic Acid Derivative, T-2054 Suppresses Osteoarthritis via Inhibiting NF-κB-Signaling Pathway.
Obeticholic Acid Derivative, T-2054 Suppresses Osteoarthritis via Inhibiting NF-κB-Signaling Pathway.
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奥贝胆酸衍生物 T-2054 通过抑制 NF-kappa B 信号通路抑制骨关节炎
DOI：
10.3390/ijms22083807
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发表时间：
2021-04-07
影响因子：
5.6
通讯作者：
Jiang W
中科院分区：
文献类型：
--
作者：
Guo D;He L;Gao Y;Jin C;Lin H;Zhang L;Wang L;Zhou Y;Yao J;Duan Y;Yang R;Qiu W;Jiang W
骨关节炎(OA)是一种退行性关节疾病，已被报道为全球最常见的残疾原因。炎性细胞因子的产生是骨性关节炎的主要因素。已有研究报道，乙酰胆酸(OCA)及其衍生物可抑制急性肝功能衰竭时促炎细胞因子的释放，但其在骨性关节炎发生发展中的作用尚未见报道。在我们的研究中，我们筛选了我们的OCA衍生物的小型合成库，发现T-2054具有抗炎特性。同时，T-2054对RAW-264.7和ATDC5细胞的增殖无明显影响。T-2054可显著降低内毒素诱导的RAW-264.7细胞释放NO以及炎性细胞因子IL-6、IL-8和肿瘤坏死因子-α的表达水平。此外，T-2054还能促进肿瘤坏死因子-α诱导的ATDC5软骨细胞细胞外基质的合成。此外，T-2054还能减轻DMM诱导的C57BL/6小鼠模型炎症细胞的浸润和软骨基质的退变，降低血清IL-6、IL-8和肿瘤坏死因子-α的水平。同时，T-2054对小鼠无明显毒性。在机制上，T-2054可降低脂多糖诱导的RAW 264.7细胞和肿瘤坏死因子-α处理的ATDC5软骨细胞中p-p65的表达。综上所述，我们首次发现T-2054通过核因子-κB信号通路有效地减少炎症介质的释放，并促进细胞外基质的合成。我们的发现支持T-2054作为一种有效的治疗药物治疗骨性关节炎的潜在用途。
Osteoarthritis (OA), a degenerative joint disorder, has been reported as the most common cause of disability worldwide. The production of inflammatory cytokines is the main factor in OA. Previous studies have been reported that obeticholic acid (OCA) and OCA derivatives inhibited the release of proinflammatory cytokines in acute liver failure, but they have not been studied in the progression of OA. In our study, we screened our small synthetic library of OCA derivatives and found T-2054 had anti-inflammatory properties. Meanwhile, the proliferation of RAW 264.7 cells and ATDC5 cells were not affected by T-2054. T-2054 treatment significantly relieved the release of NO, as well as mRNA and protein expression levels of inflammatory cytokines (IL-6, IL-8 and TNF-α) in LPS-induced RAW 264.7 cells. Moreover, T-2054 promoted extracellular matrix (ECM) synthesis in TNF-α-treated ATDC5 chondrocytes. Moreover, T-2054 could relieve the infiltration of inflammatory cells and degeneration of the cartilage matrix and decrease the levels of serum IL-6, IL-8 and TNF-α in DMM-induced C57BL/6 mice models. At the same time, T-2054 showed no obvious toxicity to mice. Mechanistically, T-2054 decreased the extent of p-p65 expression in LPS-induced RAW 264.7 cells and TNF-α-treated ATDC5 chondrocytes. In summary, we showed for the first time that T-2054 effectively reduced the release of inflammatory mediators, as well as promoted extracellular matrix (ECM) synthesis via the NF-κB-signaling pathway. Our findings support the potential use of T-2054 as an effective therapeutic agent for the treatment of OA.
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影响因子：
7
作者：
Bannuru, R. R.;Osani, M. C.;McAlindon, T. E.
通讯作者：
McAlindon, T. E.
影响因子：
5.6
作者：
Bigagli, Elisabetta;Cinci, Lorenzo;Luceri, Cristina
通讯作者：
Luceri, Cristina
DOI：
10.1002/art.39692
发表时间：
2016-07
期刊：
Arthritis & rheumatology (Hoboken, N.J.)
影响因子：
--
作者：
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通讯作者：
Boring MA
影响因子：
4.8
作者：
Ouyang, Yuanming;Wang, Wei;Li, Yanfeng
通讯作者：
Li, Yanfeng
影响因子：
168.9
作者：
da Costa, Bruno R.;Reichenbach, Stephan;Trelle, Sven
通讯作者：
Trelle, Sven