The Role Of EGR1 In The Development Of Osteoarthritis

Objective : Osteoarthritis is one of the most common orthopedic diseases in the elderly.However,its pathogenesis remains unclear.This study aimed to explore the role and mechanism of EGR1 in the progression of osteoarthritis.Methods:In this study,the relative expression of EGR1 in articular cartilage samples of osteoarthritis patients,destabilized medial meniscus(DMM)-induced osteoarthritis and 20-month-old mice were firstly detected by quantitative PCR,western blot and immunohistochemistry.The effects of EGR1 on chondrocyte hypertrophy and cartilage matrix degradation were studied by western blot,quantitative PCR,immunofluorescence and alizarin red staining.The mechanism of how EGR1 works was studied by immunoprecipitation,safranin-O-fast green staining and immunohistochemistry.The protective effect of ML264,an inhibitor of EGR1,on the development of osteoarthritis was studied in DMM-induced osteoarthritis model.Results:EGR1 expression was significantly up-regulated in articular cartilage samples from osteoarthritis patients(normal patients as control),DMM-induced osteoarthritismice(Sham group as control)and elderly mice(young mice as control).In vitro experiments indicated that IL-1? could significantly enhance EGR1 expression in primary mouse chondrocytes.EGR1 over-expression could inhibit COl2A1 expression,enhance matrix metalloproteinase expression,resulting in chondrocyte hypertrophy.Silencing EGR1,using RNAi,had the opposite effects.We investigated the underlying mechanism and found that EGR1 over-expression promoted its integration with Kruppel-like Factor 5(KLF5)protein,which inhibited the ubiquitination degradation process of KLF5 and led to the increase of KLF5 protein level.Moreover,EGR1 prompted ?-catenin nuclear transportation to control chondrocyte hypertrophy.We also found that the EGR1 inhibitor,ML264,protected chondrocytes from IL-1?-mediated cartilage matrix degradation in vitro and DMM-induced osteoarthritis in vivo.Conclusion : EGR1 promotes the cartilage degeneration and hypertrophy by activating the Kruppel-like Factor 5 and ?-catenin signaling.