Background:Knee osteoarthritis(OA)is still challenging to prevent or treat.Enhanced endoplasmic reticulum(ER)stress and increased pyroptosis in chondrocytes may be responsible for cartilage degeneration.This study aim...Background:Knee osteoarthritis(OA)is still challenging to prevent or treat.Enhanced endoplasmic reticulum(ER)stress and increased pyroptosis in chondrocytes may be responsible for cartilage degeneration.This study aims to investigate the effect of ER stress on chondrocyte pyroptosis and the upstream regulatory mechanisms,which have rarely been reported.Methods:The expression of the histone methyltransferase enhancer of zeste homolog 2(EZH2),microRNA-142-3p(miR-142-3p),and high mobility group box 1(HMGB1)and the levels of ER stress,pyroptosis,and metabolic markers in normal and OA chondrocytes were investigated by western blotting,quantitative polymerase chain reaction,immunohistochemistry,fluorescence in situ hybridization,fluorescein amidite-tyrosine-valine-alanine-aspartic acid-fluoromethyl ketone(FAM-YVAD-FMK)/Hoechst 33342/propidium iodide(PI)staining,lactate dehydrogenase(LDH)release assays,and cell viability assessments.The effects of EZH2,miR-142-3p,and HMGB1 on ER stress and pyroptosis and the hierarchical regulatory relationship between them were analyzed by chromatin immunoprecipitation,luciferase reporters,gain/loss-of-function assays,and rescue assays in interleukin(IL)-1β-induced OA chondrocytes.The mechanistic contribution of EZH2,miR-142-3p,and HMGB1 to chondrocyte ER stress and pyroptosis and therapeutic prospects were validated radiologically,histologically,and immunohistochemically in surgically induced OA rats.Results:Increased EZH2 and HMGB1,decreased miR-142-3p,enhanced ER stress,and activated pyroptosis in chondrocytes were associated with OA occurrence and progression.EZH2 and HMGB1 exacerbated and miR-142-3p alleviated ER stress and pyroptosis in OA chondrocytes.EZH2 transcriptionally silenced miR-142-3p via H3K27 trimethylation,and miR-142-3p posttranscriptionally silenced HMGB1 by targeting the 3′-UTR of the HMGB1 gene.Moreover,ER stress mediated the effects of EZH2,miR-142-3p,and HMGB1 on chondrocyte pyroptosis.In vivo experiments mechanistically validated the hierarchical regulatory relationship between EZH2,miR-142-3p,and HMGB1 and their effects on chondrocyte ER stress and pyroptosis.Conclusions:A novel EZH2/miR-142-3p/HMGB1 axis mediates chondrocyte pyroptosis and cartilage degeneration by regulating ER stress in OA,contributing novel mechanistic insights into OA pathogenesis and providing potential targets for future therapeutic research.展开更多
Background:Physical therapy is regarded as an essential aspect in achieving optimal outcomes following total knee arthroplasty(TKA).The coronavirus disease 2019(COVID-19)pandemic has made face-to-face rehabilitation i...Background:Physical therapy is regarded as an essential aspect in achieving optimal outcomes following total knee arthroplasty(TKA).The coronavirus disease 2019(COVID-19)pandemic has made face-to-face rehabilitation inaccessible.Virtual reality(VR)is increasingly regarded as a potentially effective option for offering health care interventions.This systematic review and meta-analysis investigate VR-based rehabilitation's effectiveness on outcomes following TKA.Methods:From inception to May 22,2021,PubMed/Medline,Embase,Web of Science,the Cochrane Central Register of Controlled Trials,Scopus,PsycINFO,Physiotherapy Evidence Database,China National Knowledge Infrastructure,and Wanfang were comprehensively searched to identify randomized controlled trials(RCTs)evaluating the effect of VR-based rehabilitation on patients following TKA according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement and the Cochrane Handbook for Systematic Reviews of Interventions.Results:Eight studies were included in the systematic review,and seven studies were included in the meta-analysis.VR-based rehabilitation significantly improved visual analog scale(VAS)scores within 1 month(standardized mean difference[SMD]:−0.44;95%confidence interval[CI]:−0.79 to−0.08,P=0.02),the Western Ontario and McMaster Universities Osteoarthritis Index(WOMAC)within 1 month(SMD:−0.71;95%CI:−1.03 to−0.40,P<0.01),and the Hospital for Special Surgery Knee Score(HSS)within 1 month and between 2 months and 3 months(MD:7.62;95%CI:5.77 to 9.47,P<0.01;MD:10.15;95%CI:8.03 to 12.27,P<0.01;respectively)following TKA compared to conventional rehabilitation.No significant difference was found in terms of the Timed Up and Go(TUG)test.Conclusions:VR-based rehabilitation improved pain and function but not postural control following TKA compared to conventional rehabilitation.More high-quality RCTs are needed to prove the advantage of VR-based rehabilitation.As the COVID-19 pandemic continues,it is necessary to promote this rehabilitation model.展开更多
Mitochondrial diseases represent one of the most prevalent and debilitating categories of hereditary disorders,characterized by significant genetic,biological,and clinical heterogeneity,which has driven the developmen...Mitochondrial diseases represent one of the most prevalent and debilitating categories of hereditary disorders,characterized by significant genetic,biological,and clinical heterogeneity,which has driven the development of the field of engineered mitochondria.With the growing recognition of the pathogenic role of damaged mitochondria in aging,oxidative disorders,inflammatory diseases,and cancer,the application of engineered mitochondria has expanded to those non-hereditary contexts(sometimes referred to as mitochondria-related diseases).Due to their unique non-eukaryotic origins and endosymbiotic relationship,mitochondria are considered highly suitable for gene editing and intercellular transplantation,and remarkable progress has been achieved in two promising therapeutic strategies-mitochondrial gene editing and artificial mitochondrial transfer(collectively referred to as engineered mitochondria in this review)over the past two decades.Here,we provide a comprehensive review of the mechanisms and recent advancements in the development of engineered mitochondria for therapeutic applications,alongside a concise summary of potential clinical implications and supporting evidence from preclinical and clinical studies.Additionally,an emerging and potentially feasible approach involves ex vivo mitochondrial editing,followed by selection and transplantation,which holds the potential to overcome limitations such as reduced in vivo operability and the introduction of allogeneic mitochondrial heterogeneity,thereby broadening the applicability of engineered mitochondria.展开更多
Background:Patellofemoral joint(PFJ)degeneration has traditionally been regarded as a contraindication to unicompartmental knee arthroplasty(UKA).More recently,some researchers have proposed that PFJ degeneration can ...Background:Patellofemoral joint(PFJ)degeneration has traditionally been regarded as a contraindication to unicompartmental knee arthroplasty(UKA).More recently,some researchers have proposed that PFJ degeneration can be ignored in medial UKA,and others have proposed that this change should be reviewed in PFJ degenerative facets and severity.This study aimed to systematically evaluate the effect of PFJ degeneration on patient-reported outcome measures(PROMs)and revision rates after medial UKA.Methods:Electronic databases(PubMed,Embase,Web of Science,etc.)were searched for studies assessing the influence of PFJ degeneration on medial UKA.A random-effects meta-analysis was conducted for the Oxford knee score(OKS),Knee society score(KSS),and revision rates and stratified by PFJ degenerative facets(medial/lateral/trochlear/unspecified),severe PFJ degeneration(bone exposed),and bearing type(mobile/fixed).Heterogeneity was assessed by the Cochran Q test statistic and chi-squared tests with the I-squared statistic.Results:A total of 34 articles with 7007 knees(2267 with PFJ degeneration)were included(5762 mobile-bearing and 1145 fixed-bearing and 100 unspecified).Slight to moderate degenerative changes in the medial and trochlear facets did not decrease the OKS and KSS,and only lateral facets significantly decreased the OKS(mean difference[MD]=-2.18,P<0.01)and KSS(MD=-2.61,P<0.01).The severity degree of PFJ degeneration had no additional adverse effect on the OKS,KSS,or revision rates.For mobile-bearing UKA,only lateral PFJ degeneration significantly decreased the OKS(MD=-2.21,P<0.01)and KSS(MD=-2.44,P<0.01).For fixed-bearing UKA,no correlation was found between PROMs/revision rates and PFJ degeneration.Conclusion:For medial mobile-bearing UKA,slight to moderate degenerative changes in the PFJ,except lateral facet,did not compromise PROMs or revision rates.For medial fixed-bearing UKA,although it might not be conclusive enough,PROMs or revision rates were not adversely affected by PFJ degeneration(regardless of the facet).展开更多
To the Editor:Osteoarthritis(OA)is a prominent disabling disease characterized by progressive articular cartilage damage coupled with deterioration in the subchondral bone and other structures of the joint,and is rank...To the Editor:Osteoarthritis(OA)is a prominent disabling disease characterized by progressive articular cartilage damage coupled with deterioration in the subchondral bone and other structures of the joint,and is ranked as the 12th highest disease contributing to global disability.[1]The course of knee OA is considerably long and can affect three knee compartments(the patellofemoral joint[PFJ],medial tibiofemoral joint[MTFJ],and lateral tibiofemoral joint[LTFJ])alone or in combination,resulting in a large variation in the occurrence of cartilage damage in the three compartments.[2]We aimed to determine the baseline predictors associated with distinct tricompartmental trajectories of cartilage damage in knees at risk for OA.展开更多
基金supported by the National Natural Science Foundation of China(No.81802210)the Science&Technology Department of Sichuan Province(No.2021YFS0122)+1 种基金the Health Commission of Sichuan Province(No.20PJ056)the National Clinical Research Center for Geriatrics,West China Hospital,Sichuan University(No.Z2018B20).
文摘Background:Knee osteoarthritis(OA)is still challenging to prevent or treat.Enhanced endoplasmic reticulum(ER)stress and increased pyroptosis in chondrocytes may be responsible for cartilage degeneration.This study aims to investigate the effect of ER stress on chondrocyte pyroptosis and the upstream regulatory mechanisms,which have rarely been reported.Methods:The expression of the histone methyltransferase enhancer of zeste homolog 2(EZH2),microRNA-142-3p(miR-142-3p),and high mobility group box 1(HMGB1)and the levels of ER stress,pyroptosis,and metabolic markers in normal and OA chondrocytes were investigated by western blotting,quantitative polymerase chain reaction,immunohistochemistry,fluorescence in situ hybridization,fluorescein amidite-tyrosine-valine-alanine-aspartic acid-fluoromethyl ketone(FAM-YVAD-FMK)/Hoechst 33342/propidium iodide(PI)staining,lactate dehydrogenase(LDH)release assays,and cell viability assessments.The effects of EZH2,miR-142-3p,and HMGB1 on ER stress and pyroptosis and the hierarchical regulatory relationship between them were analyzed by chromatin immunoprecipitation,luciferase reporters,gain/loss-of-function assays,and rescue assays in interleukin(IL)-1β-induced OA chondrocytes.The mechanistic contribution of EZH2,miR-142-3p,and HMGB1 to chondrocyte ER stress and pyroptosis and therapeutic prospects were validated radiologically,histologically,and immunohistochemically in surgically induced OA rats.Results:Increased EZH2 and HMGB1,decreased miR-142-3p,enhanced ER stress,and activated pyroptosis in chondrocytes were associated with OA occurrence and progression.EZH2 and HMGB1 exacerbated and miR-142-3p alleviated ER stress and pyroptosis in OA chondrocytes.EZH2 transcriptionally silenced miR-142-3p via H3K27 trimethylation,and miR-142-3p posttranscriptionally silenced HMGB1 by targeting the 3′-UTR of the HMGB1 gene.Moreover,ER stress mediated the effects of EZH2,miR-142-3p,and HMGB1 on chondrocyte pyroptosis.In vivo experiments mechanistically validated the hierarchical regulatory relationship between EZH2,miR-142-3p,and HMGB1 and their effects on chondrocyte ER stress and pyroptosis.Conclusions:A novel EZH2/miR-142-3p/HMGB1 axis mediates chondrocyte pyroptosis and cartilage degeneration by regulating ER stress in OA,contributing novel mechanistic insights into OA pathogenesis and providing potential targets for future therapeutic research.
基金This study was supported by grants from the National Natural Science Foundation of China(No.81974347)the clinical research incubation project of West China Hospital,Sichuan University(No.2018HXFH040).
文摘Background:Physical therapy is regarded as an essential aspect in achieving optimal outcomes following total knee arthroplasty(TKA).The coronavirus disease 2019(COVID-19)pandemic has made face-to-face rehabilitation inaccessible.Virtual reality(VR)is increasingly regarded as a potentially effective option for offering health care interventions.This systematic review and meta-analysis investigate VR-based rehabilitation's effectiveness on outcomes following TKA.Methods:From inception to May 22,2021,PubMed/Medline,Embase,Web of Science,the Cochrane Central Register of Controlled Trials,Scopus,PsycINFO,Physiotherapy Evidence Database,China National Knowledge Infrastructure,and Wanfang were comprehensively searched to identify randomized controlled trials(RCTs)evaluating the effect of VR-based rehabilitation on patients following TKA according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement and the Cochrane Handbook for Systematic Reviews of Interventions.Results:Eight studies were included in the systematic review,and seven studies were included in the meta-analysis.VR-based rehabilitation significantly improved visual analog scale(VAS)scores within 1 month(standardized mean difference[SMD]:−0.44;95%confidence interval[CI]:−0.79 to−0.08,P=0.02),the Western Ontario and McMaster Universities Osteoarthritis Index(WOMAC)within 1 month(SMD:−0.71;95%CI:−1.03 to−0.40,P<0.01),and the Hospital for Special Surgery Knee Score(HSS)within 1 month and between 2 months and 3 months(MD:7.62;95%CI:5.77 to 9.47,P<0.01;MD:10.15;95%CI:8.03 to 12.27,P<0.01;respectively)following TKA compared to conventional rehabilitation.No significant difference was found in terms of the Timed Up and Go(TUG)test.Conclusions:VR-based rehabilitation improved pain and function but not postural control following TKA compared to conventional rehabilitation.More high-quality RCTs are needed to prove the advantage of VR-based rehabilitation.As the COVID-19 pandemic continues,it is necessary to promote this rehabilitation model.
基金supported by the National Key R&D Program ofChina(2023YFB4606700/03)the National Natural Science Foundation ofChina(82272561)135 Project of Center for High Altitude Medicine,West China Hospital,Sichuan University(GYYX24013).
文摘Mitochondrial diseases represent one of the most prevalent and debilitating categories of hereditary disorders,characterized by significant genetic,biological,and clinical heterogeneity,which has driven the development of the field of engineered mitochondria.With the growing recognition of the pathogenic role of damaged mitochondria in aging,oxidative disorders,inflammatory diseases,and cancer,the application of engineered mitochondria has expanded to those non-hereditary contexts(sometimes referred to as mitochondria-related diseases).Due to their unique non-eukaryotic origins and endosymbiotic relationship,mitochondria are considered highly suitable for gene editing and intercellular transplantation,and remarkable progress has been achieved in two promising therapeutic strategies-mitochondrial gene editing and artificial mitochondrial transfer(collectively referred to as engineered mitochondria in this review)over the past two decades.Here,we provide a comprehensive review of the mechanisms and recent advancements in the development of engineered mitochondria for therapeutic applications,alongside a concise summary of potential clinical implications and supporting evidence from preclinical and clinical studies.Additionally,an emerging and potentially feasible approach involves ex vivo mitochondrial editing,followed by selection and transplantation,which holds the potential to overcome limitations such as reduced in vivo operability and the introduction of allogeneic mitochondrial heterogeneity,thereby broadening the applicability of engineered mitochondria.
基金National Natural Science Foundation of China(81802210 and 81672219)Key Project of Sichuan Science&Technology Department(2018SZ0223 and 2018SZ0250)National Clinical Research Center for Geriatrics,West China Hospital,Sichuan University(Z20191008 and Z2018B20)
文摘Background:Patellofemoral joint(PFJ)degeneration has traditionally been regarded as a contraindication to unicompartmental knee arthroplasty(UKA).More recently,some researchers have proposed that PFJ degeneration can be ignored in medial UKA,and others have proposed that this change should be reviewed in PFJ degenerative facets and severity.This study aimed to systematically evaluate the effect of PFJ degeneration on patient-reported outcome measures(PROMs)and revision rates after medial UKA.Methods:Electronic databases(PubMed,Embase,Web of Science,etc.)were searched for studies assessing the influence of PFJ degeneration on medial UKA.A random-effects meta-analysis was conducted for the Oxford knee score(OKS),Knee society score(KSS),and revision rates and stratified by PFJ degenerative facets(medial/lateral/trochlear/unspecified),severe PFJ degeneration(bone exposed),and bearing type(mobile/fixed).Heterogeneity was assessed by the Cochran Q test statistic and chi-squared tests with the I-squared statistic.Results:A total of 34 articles with 7007 knees(2267 with PFJ degeneration)were included(5762 mobile-bearing and 1145 fixed-bearing and 100 unspecified).Slight to moderate degenerative changes in the medial and trochlear facets did not decrease the OKS and KSS,and only lateral facets significantly decreased the OKS(mean difference[MD]=-2.18,P<0.01)and KSS(MD=-2.61,P<0.01).The severity degree of PFJ degeneration had no additional adverse effect on the OKS,KSS,or revision rates.For mobile-bearing UKA,only lateral PFJ degeneration significantly decreased the OKS(MD=-2.21,P<0.01)and KSS(MD=-2.44,P<0.01).For fixed-bearing UKA,no correlation was found between PROMs/revision rates and PFJ degeneration.Conclusion:For medial mobile-bearing UKA,slight to moderate degenerative changes in the PFJ,except lateral facet,did not compromise PROMs or revision rates.For medial fixed-bearing UKA,although it might not be conclusive enough,PROMs or revision rates were not adversely affected by PFJ degeneration(regardless of the facet).
基金the National Natural Science Foundation of China(No.81974347)National Clinical Research Center for Geriatrics,West China Hospital,Sichuan University(No.Z20191008)Science and Technology Foundation of Sichuan Province of China(No.2021YFH0094).
文摘To the Editor:Osteoarthritis(OA)is a prominent disabling disease characterized by progressive articular cartilage damage coupled with deterioration in the subchondral bone and other structures of the joint,and is ranked as the 12th highest disease contributing to global disability.[1]The course of knee OA is considerably long and can affect three knee compartments(the patellofemoral joint[PFJ],medial tibiofemoral joint[MTFJ],and lateral tibiofemoral joint[LTFJ])alone or in combination,resulting in a large variation in the occurrence of cartilage damage in the three compartments.[2]We aimed to determine the baseline predictors associated with distinct tricompartmental trajectories of cartilage damage in knees at risk for OA.
