PPARγ controls ESCRT-dependent fibroblast-like synoviocyte exosome biogenesis and Alleviates Chondrocyte Osteoarthritis Mediated by Exosomal ANXA1

Osteoarthritis (OA) is characterized by synovitis, cartilage degeneration and exercise therapy has been recognized as first line therapy. The exercise related exosome involved in the interaction between fibroblast-like synoviocytes (FLSs) and chondrocytes could be a novel promising strategy for treating OA. In this study, PPARγ was upregulated in FLSs under exercise by single cell transcriptome sequencing. Then, we investigated the underlying mechanisms of PPARγ-treated FLSs derived exosome on OA in vivo and vitro. Our data revealed that overexpression PPARγ FLSs derived exosome could ameliorate the OA severity in vivo and vitro. But knockdown PPARγ FLSs derived exosome aggravate OA. Moreover, we found PPARγ controls the endosomal sorting complex required for the transport (ESCRT)-dependent exosome biogenesis pathway. Annexin A1 (ANXA1) was enriched in OE-PPARγ exosome by quantitative proteomics. By Chip-qPCR and Co-IP methods, PPARγ and its coactivator -1α (PGC-1α) acts with ESCRT subunits including HRS, STAM1, TSG101, CHMP7 and promotes their association to cargo ANXA1. As a therapeutic cargo, exosomal ANXA1 was confirmed be internalization by chondrocyte via exosome labeled experiment and ANXA1 could inhibit the phospharylation of ERK to activate the autophagy and decrease chondrocyte apoptosis. While the ANXA1 receptor blocker BOC-2 could reverse the therapic effect. In conclusion, PPARγ/ESCRT – FLSs exosomal ANXA1 – ERK axis provides a deeper theoretical basis for exercise therapy of OA and a new idea for the clinical transformation of exosomes into OA therapy.