Infrapatellar fat pad exosomes promote osteoarthritis by reprogramming macrophage polarization.

The infrapatellar fat pad (IPFP) is a crucial mediator in knee osteoarthritis (OA), but the mechanisms of its pathogenic signaling remain elusive. This study investigates the role of IPFP-derived exosomes in OA progression. We found that exosomes from end-stage OA patient IPFP (OA-EXOs) were secreted abundantly. In vitro, OA-EXOs were internalized by macrophages, reprogramming them to a pro-inflammatory M1 phenotype while inhibiting anti-inflammatory M2 polarization, thereby creating a catabolic microenvironment that disrupted chondrocyte extracellular matrix homeostasis. Furthermore, OA-EXOs directly targeted chondrocytes, activating the Notch pathway to promote inflammatory responses and metabolic dysfunction. In a murine OA model, intra-articular injection of OA-EXOs exacerbated cartilage destruction and subchondral bone sclerosis. Mechanistically, miR-342-5p was highly enriched in OA-EXOs. It orchestrated macrophage polarization by directly targeting TRAF3 and inhibiting the downstream STAT6-PPARγ axis. In chondrocytes, miR-342-5p activated the Notch pathway. Importantly, therapeutic inhibition of miR-342-5p in vivo restored TRAF3 expression, promoted M2 macrophage polarization, and attenuated OA progression. Our findings unveil a novel pathogenic mechanism in which IPFP exosomes deliver miR-342-5p to coordinately disrupt immune-metabolic homeostasis in the joint, identifying the miR-342-5p-TRAF3 axis as a promising therapeutic target for OA.