Extracellular vesicles from IPFP-MSCs trigger osteoarthritis by transferring mtDNA

Infrapatellar fat pad mesenchymal stem cells (IPFP-MSCs) extracellular vesicles (EVs) are found to be capable of accelerating Osteoarthritis (OA) progression. However, which pathways and which pathogenic EVs subgroups are involved are not defined. In our study we found that there were a higher percentage of TOMM20⁺ EV's within the total synovial fluid EV's from OA patients than from trauma patients as well as increased mtDNA content. This implicates the mitochondria derived EV sub-group - mitochondria derived vesicles (MDVs) as a potential driver in OA. We found with the single-cell data that MDVs may be secreted from IPFP-MSCs with VPS35. Furthermore, these cells were harvested from the body of the OA patient. IPFP-MSC derived MDVs can deliver exogenous mtDNA to chondrocytes by fusing directly, thus inhibiting chondrocyte matrix synthesis, inducing mitochondrial dysfunction, and activating pro-inflammatory signaling cascades in chondrocytes. Protein microarrays showed that MDVs delivered exogenous mtDNA to chondrocytes, which then activated the cGAS-STING pathway and downstream inflammatory mediators (TBK1, NF-κB, TNF-α). Intra-articular MDV injection worsened cartilage degradation and synovitis in OA rats but STING inhibition alleviated them. This study showed that IPFP-MSC-derived MDVs are essential for OA pathogenesis via mtDNA transfer and cGAS-STING pathway activation. These results show how the mitochondria and immune system talk to each other in the joints causing pain and destroying the cartilage, MDVs are new things that can tell us if someone has this disease and help doctors fix it. Pharmacological blockade of the cGAS-STING axis has shown therapeutic potential, providing a dual approach to mitigate mitochondrial stress and innate immune hyperactivation in OA.