首页|Isorhamnetin Downregulates MMP2 and MMP9 to Inhibit Development of Rheumatoid Arthritis through SRC/ERK/CREB Pathway
Isorhamnetin Downregulates MMP2 and MMP9 to Inhibit Development of Rheumatoid Arthritis through SRC/ERK/CREB Pathway
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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 40 μmol/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-1 β,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-1 β in 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-1 β(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-1 β,as well as the phosphorylation of SRC,ERK,and CREB in synovial tissue(P＜0.05).Notably,the inhibitory effect of isorhamnetin was more pronounced at higher concentrations(P＜0.05).Conclusion:Isorhamnetin exhibited anti-RA effects through modulating SRC/ERK/CREB and MMP2/MMP9 signaling pathways,suggesting that isorhamnetin may be a potential therapeutic agent for RA.
LIU Xiao-rong、LI Shuo-fu、MEI Wen-ya、LIU Xiang-dan、ZHOU Ri-bao
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College of Pharmacy,Hunan University of Chinese Medicine,Changsha(410208),China
Department of Orthopaedics,The First Hospital of Hunan University of Chinese Medicine,Changsha(410007),China
湖南省自然科学基金湖南省自然科学基金Project of Hunan Provincial Health and Health CommissionProject of Hunan Provincial Student Innovation and Entrepreneurship Training ProgramHunan Provincial Administration of Traditional Chinese Medicine Scientific Research ProgramHunan University of Traditional Chinese Medicine Primary Discipline Open Fund Project in Chinese MedicineKey Discipline Project on Chinese Pharmacology of Hunan University of Chinese MedicineScientific Research Project of Hunan Provincial Administration of Traditional Chinese Medicine
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