CP-25 monotherapy and combined administration ameliorate progression of animal arthritis model by inhibition on GRK2 translocation

作     者：YANG Xue-zhi ZHAO Ying-jie SU Su-li WANG Chun WU Yu-jing ZHANG Ling-ling CHANG Yan WEI Wei 

作者机构：Institute of Clinical PharmacologyAnhui Medical UniversityKey Laboratory of Anti-inflammatory and Immune Medicine(Anhui Medical University)Ministry of EducationAnhui Collaborative Innovation Center of Anti-inflammatory and Immune Medicine 

出 版 物：《中国药理学与毒理学杂志》 (Chinese Journal of Pharmacology and Toxicology)

年 卷 期：2019年第33卷第9期

页      面：669-670页

学科分类：1002[医学-临床医学] 100201[医学-内科学(含：心血管病、血液病、呼吸系病、消化系病、内分泌与代谢病、肾病、风湿病、传染病)] 10[医学] 

基　　金：National Natural Science Foundation of China(81330081 81673444 31200675 81573443) Anhui Province Natural Science Fund(outstanding youth)(170808J10) Key Projects of Outstanding young Talent Support Program in Colleges and Universities(gxyq ZD2016043) 

主　　题：CP-25 drug combination GRK2 p-ERK EP4 

摘      要：OBJECTIVE Increased efficacy without increased toxicity is expected when treating rheumatoid arthritis(RA).However,there are many difficulties associated with currently available RA ***,CP-25,a new compound developed by our group,significantly inhibits the progression of arthritis in animal models through reducing membrane expression of *** study observed CP-25 monotherapy and combined administration with MTX/LEF in treating animal arthritis model and investigated possible *** We set up AA rat and collageninduced arthritis(CIA)mice *** groups were divided into normal group,vehicle group,monotherapy groups and CP-25-combined MTX/LEF *** focused on the role of GRK2 on macrophage polarization and fibro⁃blast-like synoviocytes(FLS)*** measured cytokine levels,phosphorylation and protein expression,and interactions between *** disruption of GRK2 in FLS and macrophages through GRK2 siRNA and CRIS⁃PR/*** Equivalent therapeutic effects were observed between CP-25-combination groups and high-dose MTX/LEF *** the vehicle group,GRK2 membrane expression increased leading to the decreased GRK2-p-ERK interactions in FLS(leading to the phosphorylation of ERK related with FLS over-proliferation),and increased GRK2-EP4 interaction in macrophage(leading to the abnormal PGE2-EP4-cAMP-CREB signal related with imbalance of macro⁃phage polarization).CONCLUSION CP-25 monotherapy and combined administration with MTX/LEF ameliorate the progression of animal arthritis ***-25 inhibited p-ERK by reducing the membrane expression of GRK2 in FLS from AA ***-25 restored normal PGE2-EP4-cAMP-CREB signal through inhibiting GRK2 transferring to *** results highlighted CP-25 a kind of potential for treating patients with RA.