Osteoarthritis(OA)is the most prevalent chronic degenerative joint disease with few treatment options.The pathogenesis of OA is characterized by sustained inflammation,oxidative stress and chondrocyte apoptosis that eventually lead to cartilage degradation and joint dysfunction.In the present study,we identified a synthetic triterpenoid CDDO-Im(1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl]imidazole)as an activator of Nrf2(nuclear factor erythroid 2-related factor 2)that displayed strong anti-OA effects.We showed that CDDO-Im(20 nM)significantly alleviated TNF-α-induced apoptosis of primary human chondrocytes and extracellular matrix degradation.In a mouse OA model incurred by DMM(destabilization of medial meniscus),administration of CDDO-Im(2.5 mg/kg,ip,every other day for 8 weeks)effectively reduced knee joint cartilage erosion and serum levels of inflammatory cytokines IL-1 β and IL-6.We revealed that CDDO-Im(20 nM)significantly enhanced autophagy activities in chondrocytes,whereas the autophagy inhibition by chloroquine(CQ,50 μM)or 3-methyladenine(3-MA,5 mM)abrogated the anti-apoptosis and chondroprotective effects of CDDO-Im in TNF-α-treated chondrocytes.Moreover,we confirmed that CDDO-Im(1-20 nM)dose-dependently activated Nrf2 pathway in TNF-α-treated chondrocytes,and its chondroprotective and autophagy-enhancing effects were significantly diminished when Nrf2 signaling was blocked by Nrf2 inhibitor ML385(20 μM)or siRNA-mediated Nrf2 knockdown.Together,our results demonstrate that CDDO-Im exhibits prominent chondroprotective and anti-OA activities owing to its Nrf2 activation and autophagy-enhancing properties,which might provide new insights into the strategies of OA clinical prevention and treatment.

Jian Dong;Kai-jia Zhang;Gao-cai Li;Xing-ren Chen;Jia-jia Lin;Jia-wei Li;Zhong-yang Lv;Zhao-zhi Deng;Jin Dai;Wangsen Cao;Qing Jiang

Division of Sports Medicine and Adult Reconstructive Surgery,Department of Orthopedic Surgery,State Key Laboratory of Pharmaceutical Biotechnology,Nanjing Drum Tower Hospital,The Affiliated Hospital of Nanjing University Medical School,Nanjing 210008,China;Department of Orthopedics,Union Hospital,Tongji Medical College,Huazhong University of Science and Technology,Wuhan 430022,China;Department of Critical Care Medicine,Jinling Hospital,School of Medicine,Nanjing University Medical School,Nanjing 210003,China;Center for Organ Fibrosis and Remodeling Research,Jiangsu Key Lab of Molecular Medicine,Nanjing University Medical School,Nanjing 210093,China

中国药理学报（英文版）

[1]Jian Dong;Kai-jia Zhang;Gao-cai Li;Xing-ren Chen;Jia-jia Lin;Jia-wei Li;Zhong-yang Lv;Zhao-zhi Deng;Jin Dai;Wangsen Cao;Qing Jiang-.CDDO-Im ameliorates osteoarthritis and inhibits chondrocyte apoptosis in mice via enhancing Nrf2-dependent autophagy)[J].中国药理学报（英文版）,2022(07):1793-1802

CDDO,dioxooleana,oyl,chondroprotective

Im,ameliorates,osteoarthritis,inhibits,apoptosis,mice,enhancing,Nrf2,autophagy,Osteoarthritis,OA,most,prevalent,chronic,degenerative,joint,disease,few,treatment,options,pathogenesis,characterized,by,sustained,inflammation,oxidative,stress,that,eventually,lead,cartilage,degradation,dysfunction,In,present,study,identified,synthetic,triterpenoid,cyano,dien,imidazole,activator,nuclear,erythroid,related,displayed,strong,anti,effects,We,showed,nM,significantly,alleviated,induced,primary,human,chondrocytes,extracellular,matrix,mouse,model,incurred,DMM,destabilization,medial,meniscus,administration,ip,every,other,day,weeks,effectively,reduced,knee,erosion,serum,levels,inflammatory,cytokines,revealed,enhanced,activities,whereas,inhibition,chloroquine,CQ,methyladenine,MA,mM,abrogated,treated,Moreover,confirmed,dose,dependently,activated,pathway,were,diminished,when,signaling,was,blocked,inhibitor,ML385,siRNA,mediated,knockdown,Together,our,results,demonstrate,exhibits,prominent,owing,activation,properties,which,might,provide,new,insights,into,strategies,clinical,prevention

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