Extracellular vesicles from IPFP-MSCs trigger osteoarthritis by transferring mtDNA

Area of Science:

• Mitochondrial biology
• Immunology
• Extracellular vesicles research

Background:

• Osteoarthritis (OA) progression is accelerated by extracellular vesicles (EVs) from infrapatellar fat pad mesenchymal stem cells (IPFP-MSCs).
• The specific pathogenic EV subgroups and pathways driving OA remain undefined.
• Mitochondria-derived vesicles (MDVs) are implicated due to increased TOMM20+ EVs and mtDNA content in OA synovial fluid.

Purpose of the Study:

• To identify pathogenic EV subgroups driving OA.
• To elucidate the role of mitochondria-derived vesicles (MDVs) in OA pathogenesis.
• To investigate the therapeutic potential of targeting the cGAS-STING pathway in OA.

Main Methods:

• Analysis of synovial fluid EVs from OA and trauma patients.
• Single-cell RNA sequencing to identify MDV-secreting cells.
• In vitro studies using chondrocytes and IPFP-MSC-derived MDVs.
• Protein microarray analysis to identify activated pathways.
• In vivo studies using an OA rat model with STING inhibition.

Main Results:

• A higher percentage of TOMM20+ EVs and increased mtDNA content were observed in OA patient synovial fluid.
• IPFP-MSCs expressing VPS35 were identified as a source of MDVs.
• IPFP-MSC-derived MDVs delivered exogenous mtDNA to chondrocytes, inhibiting matrix synthesis and inducing mitochondrial dysfunction.
• MDVs activated the cGAS-STING pathway and downstream inflammatory mediators in chondrocytes.
• Intra-articular MDV injection exacerbated OA in rats, while STING inhibition alleviated symptoms.

Conclusions:

• IPFP-MSC-derived MDVs are key drivers of OA pathogenesis through mtDNA transfer and cGAS-STING pathway activation.
• The study reveals crosstalk between mitochondria and the immune system in OA joint pathology.
• Targeting the cGAS-STING axis offers a potential therapeutic strategy for OA by mitigating mitochondrial stress and inflammation.