GrpE-like 1(GRPEL1)-carrying exosomes derived from synovial mesenchymal stem cells(SMSC)prevent mitochondrial dysfunction associated with osteoarthritis(OA)by activating PINK1-mediated mitophagy,restoring chondrocyte ...GrpE-like 1(GRPEL1)-carrying exosomes derived from synovial mesenchymal stem cells(SMSC)prevent mitochondrial dysfunction associated with osteoarthritis(OA)by activating PINK1-mediated mitophagy,restoring chondrocyte function,and preserving the extracellular matrix both in vitro and in vivo.Bioinformatics analysis of human OA datasets identified GRPEL1 as a mitophagyrelated gene that is downregulated in OA.Exosomes enriched with GRPEL1 derived from SMSCs enhanced mitochondrial membrane potential and ATP production,reduced lipid peroxidation and reactive oxygen species,increased mitophagy markers(PINK1,Parkin,LC3-II/I),decreased p62 levels,and alleviated cartilage degeneration in a rat destabilization model.A causal role for mitophagy is supported by coimmunoprecipitation experiments confirming a GRPEL1-PINK1 interaction,and by PINK1 knockdown,which diminishes the protective effects of GRPEL1.These findings suggest that exosomes enriched with GRPEL1 derived from SMSCs represents a promising disease-modifying approach for OA by targeting mitochondrial quality control.展开更多
BACKGROUND Osteoarthritis(OA)remains a challenging degenerative joint disease with limited therapeutic interventions.AIM To investigate the potential of synovial mesenchymal stem cell(SMSC)-derived exosomes(SMSCs-Exos...BACKGROUND Osteoarthritis(OA)remains a challenging degenerative joint disease with limited therapeutic interventions.AIM To investigate the potential of synovial mesenchymal stem cell(SMSC)-derived exosomes(SMSCs-Exos)delivering GrpE-like 1(GRPEL1)in promoting cartilage repair through phosphatase and tensin homolog-induced putative kinase 1(PINK1)-mediated mitophagy activation.METHODS A comprehensive research approach was employed,including bioinformatics analysis of gene expression datasets(GSE169077 and GSE114007),in vitro ex-periments with CHON-001 chondrocytes,and in vivo rat knee OA models.Experi-mental techniques encompassed gene expression profiling,immunofluorescence staining,western blot analysis,co-immunoprecipitation,cell proliferation and migration assays,and histological examinations.Exosomes were genetically modified to overexpress or knockdown GRPEL1,and their effects on cellular function and mitochondrial dynamics were systematically evaluated.RESULTS Bioinformatics analysis revealed GRPEL1 as a critical mitophagy-related gene with significantly altered expression in OA.In vitro studies demonstrated that GRPEL1-loaded SMSCs-Exos effectively counteracted interleukin-1 beta-induced cellular damage by enhancing chondrocyte proliferation and migration,preserving extracellular matrix integrity.Mechanistic investigations confirmed direct interaction between GRPEL1 and PINK1,leading to enhanced mitophagy activation.In vivo rat models substantiated these findings,showing significantly reduced cartilage damage,restored proteoglycan content,and improved joint structure in groups receiving GRPEL1-overexpressing exosomes.Key molecular changes included decreased reactive oxygen species,improved mitochondrial membrane potential,and increased mitophagy markers.CONCLUSION This study provides compelling evidence that SMSCs-Exos delivering GRPEL1 can effectively activate PINK1-mediated mitophagy,offering a promising therapeutic strategy for cartilage repair in OA.The research unveils a novel molecular mechanism for targeting mitochondrial dysfunction and presents a potential disease-modifying approach beyond current symptomatic treatments.展开更多
基金Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Education,No.NRF-2022R1I1A1A01068652.
文摘GrpE-like 1(GRPEL1)-carrying exosomes derived from synovial mesenchymal stem cells(SMSC)prevent mitochondrial dysfunction associated with osteoarthritis(OA)by activating PINK1-mediated mitophagy,restoring chondrocyte function,and preserving the extracellular matrix both in vitro and in vivo.Bioinformatics analysis of human OA datasets identified GRPEL1 as a mitophagyrelated gene that is downregulated in OA.Exosomes enriched with GRPEL1 derived from SMSCs enhanced mitochondrial membrane potential and ATP production,reduced lipid peroxidation and reactive oxygen species,increased mitophagy markers(PINK1,Parkin,LC3-II/I),decreased p62 levels,and alleviated cartilage degeneration in a rat destabilization model.A causal role for mitophagy is supported by coimmunoprecipitation experiments confirming a GRPEL1-PINK1 interaction,and by PINK1 knockdown,which diminishes the protective effects of GRPEL1.These findings suggest that exosomes enriched with GRPEL1 derived from SMSCs represents a promising disease-modifying approach for OA by targeting mitochondrial quality control.
基金Supported by the Scientific Research Project of the Traditional Chinese Medicine Administration of Hubei Provincial Health Commission,No.ZY2025 L268.
文摘BACKGROUND Osteoarthritis(OA)remains a challenging degenerative joint disease with limited therapeutic interventions.AIM To investigate the potential of synovial mesenchymal stem cell(SMSC)-derived exosomes(SMSCs-Exos)delivering GrpE-like 1(GRPEL1)in promoting cartilage repair through phosphatase and tensin homolog-induced putative kinase 1(PINK1)-mediated mitophagy activation.METHODS A comprehensive research approach was employed,including bioinformatics analysis of gene expression datasets(GSE169077 and GSE114007),in vitro ex-periments with CHON-001 chondrocytes,and in vivo rat knee OA models.Experi-mental techniques encompassed gene expression profiling,immunofluorescence staining,western blot analysis,co-immunoprecipitation,cell proliferation and migration assays,and histological examinations.Exosomes were genetically modified to overexpress or knockdown GRPEL1,and their effects on cellular function and mitochondrial dynamics were systematically evaluated.RESULTS Bioinformatics analysis revealed GRPEL1 as a critical mitophagy-related gene with significantly altered expression in OA.In vitro studies demonstrated that GRPEL1-loaded SMSCs-Exos effectively counteracted interleukin-1 beta-induced cellular damage by enhancing chondrocyte proliferation and migration,preserving extracellular matrix integrity.Mechanistic investigations confirmed direct interaction between GRPEL1 and PINK1,leading to enhanced mitophagy activation.In vivo rat models substantiated these findings,showing significantly reduced cartilage damage,restored proteoglycan content,and improved joint structure in groups receiving GRPEL1-overexpressing exosomes.Key molecular changes included decreased reactive oxygen species,improved mitochondrial membrane potential,and increased mitophagy markers.CONCLUSION This study provides compelling evidence that SMSCs-Exos delivering GRPEL1 can effectively activate PINK1-mediated mitophagy,offering a promising therapeutic strategy for cartilage repair in OA.The research unveils a novel molecular mechanism for targeting mitochondrial dysfunction and presents a potential disease-modifying approach beyond current symptomatic treatments.
