Isorhamnetin Downregulates MMP2 and MMP9 to Inhibit Development of Rheumatoid Arthritis through SRC/ERK/CREB Pathway  

作　　者：LIU Xiao-rong LI Shuo-fu MEI Wen-ya LIU Xiang-dan ZHOU Ri-bao 

机构地区：[1]College of Pharmacy,Hunan University of Chinese Medicine,Changsha(410208),China [2]Department of Orthopaedics,The First Hospital of Hunan University of Chinese Medicine,Changsha(410007),China

出　　处：《Chinese Journal of Integrative Medicine》2024年第4期299-310,共12页中国结合医学杂志（英文版）

基　　金：Supported by the Natural Science Foundation of Hunan Province(Nos.2022JJ80086 and 2023JJ60342);the Project of Hunan Provincial Health and Health Commission(No.D202302078705);the Project of Hunan Provincial Student Innovation and Entrepreneurship Training Program(No.2022-5313);the Hunan Provincial Administration of Traditional Chinese Medicine Scientific Research Program(No.2021161);the Hunan University of Traditional Chinese Medicine Primary Discipline Open Fund Project in Chinese Medicine(No.2020ZYX01);the Key Discipline Project on Chinese Pharmacology of Hunan University of Chinese Medicine(No.202302);the Scientific Research Project of Hunan Provincial Administration of Traditional Chinese Medicine(No.B2023150)。

摘　　要：Objective To investigate the effect of isorhamnetin on the pathology of rheumatoid arthritis(RA).Methods Tumor necrosis factor(TNF)-α-induced fibroblast-like synoviocytes(FLS)was exposed to additional isorhamnetin(10,20 and 40µmol/L).Overexpression vectors for matrix metalloproteinase-2(MMP2)or MMP9 or SRC were transfected to explore their roles in isorhamnetin-mediated RA-FLS function.RA-FLS viability,migration,and invasion were evaluated.Moreover,a collagen-induced arthritis(CIA)rat model was established.Rats were randomly divided to sham,CIA,low-,medium-,and high-dosage groups using a random number table(n=5 in each group)and administed with normal saline or additional isorhamnetin[2,10,and 20 mg/(kg·day)]for 4 weeks,respectively.Arthritis index was calculated and synovial tissue inflammation was determined in CIA rats.The levels of MMP2,MMP9,TNF-α,interleukin-6(IL-6),and IL-1β,as well as the phosphorylation levels of SRC,extracellular regulated kinase(ERK),and cyclic adenosine monophosphate response element-binding(CREB),were detected in RA-FLS and synovial tissue.Molecular docking was also used to analyze the binding of isorhamnetin to SRC.Results In in vitro studies,isorhamnetin inhibited RA-FLS viability,migration and invasion(P<0.05).Isorhamnetin downregulated the levels of MMP2,MMP9,TNF-α,IL-6,and IL-1βin RA-FLS(P<0.05).The overexpression of either MMP2 or MMP9 reversed isorhamnetin-inhibited RA-FLS migration and invasion,as well as the levels of TNF-α,IL-6,and IL-1β(P<0.05).Furthermore,isorhamnetin bound to SRC and reduced the phosphorylation of SRC,ERK,and CREB(P<0.05).SRC overexpression reversed the inhibitory effect of isorhamnetin on RA-FLS viability,migration and invasion,as well as the negative regulation of MMP2 and MMP9(P<0.05).In in vivo studies,isorhamnetin decreased arthritis index scores(P<0.05)and alleviated synovial inflammation.Isorhamnetin reduced the levels of MMP2,MMP9,TNF-α,IL-6,and IL-1β,as well as the phosphorylation of SRC,ERK,and CREB in synovial tissue(P<0.05).Notably,

关 键 词：rheumatoid arthritis ISORHAMNETIN SRC/ERK/CREB matrix metalloproteinase 

分 类 号：R285[医药卫生—中药学]