Adipose-derived extracellular vesicles RBP4 aggravates osteoarthritis by inducing chondrocyte mitochondrial...

Osteoarthritis (OA) is a degenerative joint disorder strongly exacerbated by obesity, but the underlying metabolic mechanisms remain unclear. This study hypothesized that extracellular vesicles (EVs) from obese adipose tissue (AT-EVs) deliver the adipokine Retinol-Binding Protein 4 (RBP4) to chondrocytes, thereby inducing mitochondrial dysfunction and promoting OA pathogenesis. A high-fat diet (HFD)-induced obesity model and a surgical OA model in mice were established to investigate this pathway. AT-EVs isolated from HFD mice was found to significantly exacerbate cartilage degradation and synovitis in vivo. In vitro, these EVs promoted an inflammatory and catabolic phenotype, increased apoptosis, and induced severe mitochondrial dysfunction in TNF-α-stimulated chondrocytes. RBP4 was identified as the key pathogenic cargo, and its effects were linked to the PI3K/AKT and JAK2/STAT3 signaling activation. Crucially, EVs derived from mice with an adipocyte-specific knockdown of RBP4 lost their pathological effects, successfully rescuing chondrocytes viability, restoring extracellular matrix homeostasis, and alleviating mitochondrial dysfunction. RBP4 enrichment in adipose-derived EVs plays a critical role in promoting OA progression in vivo. Our findings reveal that RBP4 from EVs of obese adipose tissue is a critical mediator of OA pathogenesis, acting through the induction of mitochondrial dysfunction in chondrocytes. This pathway represents a novel and specific therapeutic target for obesity-associated OA.