首页 | 官方网站   微博 | 高级检索  
     


Obeticholic Acid Derivative,T-2054 Suppresses Osteoarthritis via Inhibiting NF-κB-Signaling Pathway
Authors:Dandan Guo  Liming He  Yaoxin Gao  Chenxu Jin  Haizhen Lin  Li Zhang  Liting Wang  Ying Zhou  Jie Yao  Yixin Duan  Renzheng Yang  Wenwei Qiu  Wenzheng Jiang
Affiliation:1.Department of Shanghai Key Laboratory of Regulatory Biology, East China Normal University, Shanghai 200241, China; (D.G.); (Y.G.); (C.J.); (H.L.); (L.Z.); (Y.Z.); (J.Y.); (Y.D.); (R.Y.);2.Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, 3663 North Zhongshan Road, Shanghai 200062, China; (L.H.); (L.W.)
Abstract: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.
Keywords:T-2054  osteoarthritis  RAW 264  7 cell line  ATDC5 chondrocytes  NF-κ  B-signaling
设为首页 | 免责声明 | 关于勤云 | 加入收藏

Copyright©北京勤云科技发展有限公司    京ICP备09084417号-23

京公网安备 11010802026262号