Synovial mesenchymal stem cell-derived exosomes delivering GRPEL1 activate PINK1-mediated mitophagy to promote cartilage repair in arthritis

Abstract

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 experiments with CHON-001 chondrocytes, and in vivo rat knee OA models. Experimental 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.

Keywords: Osteoarthritis; Exosomes; Synovial mesenchymal stem cell; Cartilage repair; GrpE-like 1; Phosphatase and tensin homolog-induced putative kinase 1

Core Tip: This study demonstrates that synovial mesenchymal stem cell-derived exosomes engineered to deliver GrpE-like 1 effectively enhance phosphatase and tensin homolog-induced putative kinase 1-mediated mitophagy, promoting cartilage repair in osteoarthritis. By integrating bioinformatics, in vitro chondrocyte assays, and in vivo rat models, the findings reveal a novel mechanism by which GrpE-like 1 activates mitochondrial quality control and reduces oxidative stress. This work introduces a promising exosome-based therapeutic strategy that targets mitochondrial dysfunction, advancing the development of disease-modifying treatments beyond current symptomatic approaches for osteoarthritis.