Macrophage polarization and energy metabolic reprogramming play pivotal roles in the onset and progression of inflammatory arthritis.Moreover,although previous studies have reported that the proviral integration of Mo...Macrophage polarization and energy metabolic reprogramming play pivotal roles in the onset and progression of inflammatory arthritis.Moreover,although previous studies have reported that the proviral integration of Moloney virus 2(Pim2)kinase is involved in various cancers through the mediation of aerobic glycolysis in cancer cells,its role in inflammatory arthritis remains unclear.In this study,we demonstrated that multiple metabolic enzymes are activated upon Pim2 upregulation during M1 macrophage polarization.Specifically,Pim2 directly phosphorylates PGK1-S203,PDHA1-S300,and PFKFB2-S466,thereby promoting glycolytic reprogramming.Pim2 expression was elevated in macrophages from patients with inflammatory arthritis and collageninduced arthritis(CIA)model mice.Conditional knockout of Pim2 in macrophages or administration of the Pim2 inhibitor HJ-PI01 attenuated arthritis development by inhibiting M1 macrophage polarization.Through molecular docking and dynamic simulation,bexarotene was identified as an inhibitor of Pim2 that inhibits glycolysis and downstream M1 macrophage polarization,thereby mitigating the progression of inflammatory arthritis.For targeted treatment,neutrophil membrane-coated bexarotene(Bex)-loaded PLGA-based nanoparticles(NM@NP-Bex)were developed to slow the progression of inflammatory arthritis by suppressing the polarization of M1 macrophages,and these nanoparticles(NPs)exhibited superior therapeutic effects with fewer side effects.Taken together,the results of our study demonstrated that targeting Pim2 inhibition could effectively alleviate inflammatory arthritis via glycolysis inhibition and reversal of the M1/M2 macrophage imbalance.NM@NPs loaded with bexarotene could represent a promising targeted strategy for the treatment of inflammatory arthritis.展开更多
Several types of arthritis share the common feature that the generation of inflammatory mediators leads to joint cartilage degradation.However,the shared mechanism is largely unknown.H2BK120ub1 was reportedly involved...Several types of arthritis share the common feature that the generation of inflammatory mediators leads to joint cartilage degradation.However,the shared mechanism is largely unknown.H2BK120ub1 was reportedly involved in various inflammatory diseases but its role in the shared mechanism in inflammatory joint conditions remains elusive.The present study demonstrated that levels of cartilage degradation,H2BK120ub1,and its regulator WW domain-containing adapter protein with coiled-coil(WAC)were increased in cartilage in human rheumatoid arthritis(RA)and osteoarthritis(OA)patients as well as in experimental RA and OA mice.By regulating H2BK120ub1 and H3K27me3,WAC regulated the secretion of inflammatory and cartilage-degrading factors.WAC influenced the level of H3K27me3 by regulating nuclear entry of the H3K27 demethylase KDM6B,and acted as a key factor of the crosstalk between H2BK120ub1 and H3K27me3.The cartilage-specific knockout of WAC demonstrated the ability to alleviate cartilage degradation in collagen-induced arthritis(CIA)and collagenase-induced osteoarthritis(CIOA)mice.Through molecular docking and dynamic simulation,doxercalciferol was found to inhibit WAC and the development of cartilage degradation in the CIA and CIOA models.Our study demonstrated that WAC is a key factor of cartilage degradation in arthritis,and targeting WAC by doxercalciferol could be a viable therapeutic strategy for treating cartilage destruction in several types of arthritis.展开更多
基金supported by the National Natural Science Foundation of China(No.82172385 to HS)National Natural Science Foundation of China(No.82172349 to YW)+4 种基金Guangdong Provincial Clinical Research Center for Orthopedic Diseases(No.2023B110001 to HS)Futian Healthcare Research Project(No.FTWS2022020 to JL)Futian Healthcare Research Project(No.FTWS2023058 to JL)Guangdong Natural Science Foundation(No.2023A1515010531 to JL)Shenzhen Science and Technology Program(No.KCXFZ20230731092959001 to PW).
文摘Macrophage polarization and energy metabolic reprogramming play pivotal roles in the onset and progression of inflammatory arthritis.Moreover,although previous studies have reported that the proviral integration of Moloney virus 2(Pim2)kinase is involved in various cancers through the mediation of aerobic glycolysis in cancer cells,its role in inflammatory arthritis remains unclear.In this study,we demonstrated that multiple metabolic enzymes are activated upon Pim2 upregulation during M1 macrophage polarization.Specifically,Pim2 directly phosphorylates PGK1-S203,PDHA1-S300,and PFKFB2-S466,thereby promoting glycolytic reprogramming.Pim2 expression was elevated in macrophages from patients with inflammatory arthritis and collageninduced arthritis(CIA)model mice.Conditional knockout of Pim2 in macrophages or administration of the Pim2 inhibitor HJ-PI01 attenuated arthritis development by inhibiting M1 macrophage polarization.Through molecular docking and dynamic simulation,bexarotene was identified as an inhibitor of Pim2 that inhibits glycolysis and downstream M1 macrophage polarization,thereby mitigating the progression of inflammatory arthritis.For targeted treatment,neutrophil membrane-coated bexarotene(Bex)-loaded PLGA-based nanoparticles(NM@NP-Bex)were developed to slow the progression of inflammatory arthritis by suppressing the polarization of M1 macrophages,and these nanoparticles(NPs)exhibited superior therapeutic effects with fewer side effects.Taken together,the results of our study demonstrated that targeting Pim2 inhibition could effectively alleviate inflammatory arthritis via glycolysis inhibition and reversal of the M1/M2 macrophage imbalance.NM@NPs loaded with bexarotene could represent a promising targeted strategy for the treatment of inflammatory arthritis.
基金supported by the Guangdong Provincial Clinical Research Center for Orthopedic Diseases(2023B110001,China)the National Natural Science Foundation of China(82172349,82002267,82102529)+2 种基金the Project Supported by Guangdong Natural Science Foundation(2023A1515010531,China)the Shenzhen Science and Technology Program(JCYJ20210324115007019,RCBS20221008093103013,China)Futian Healthcare Research Project(FTWS2022020,FTWS2023058,China).
文摘Several types of arthritis share the common feature that the generation of inflammatory mediators leads to joint cartilage degradation.However,the shared mechanism is largely unknown.H2BK120ub1 was reportedly involved in various inflammatory diseases but its role in the shared mechanism in inflammatory joint conditions remains elusive.The present study demonstrated that levels of cartilage degradation,H2BK120ub1,and its regulator WW domain-containing adapter protein with coiled-coil(WAC)were increased in cartilage in human rheumatoid arthritis(RA)and osteoarthritis(OA)patients as well as in experimental RA and OA mice.By regulating H2BK120ub1 and H3K27me3,WAC regulated the secretion of inflammatory and cartilage-degrading factors.WAC influenced the level of H3K27me3 by regulating nuclear entry of the H3K27 demethylase KDM6B,and acted as a key factor of the crosstalk between H2BK120ub1 and H3K27me3.The cartilage-specific knockout of WAC demonstrated the ability to alleviate cartilage degradation in collagen-induced arthritis(CIA)and collagenase-induced osteoarthritis(CIOA)mice.Through molecular docking and dynamic simulation,doxercalciferol was found to inhibit WAC and the development of cartilage degradation in the CIA and CIOA models.Our study demonstrated that WAC is a key factor of cartilage degradation in arthritis,and targeting WAC by doxercalciferol could be a viable therapeutic strategy for treating cartilage destruction in several types of arthritis.
