Circulating Metabolites Treat Human TMJ-OA by Eliminating Senescent Chondrocytes via the C1QBP/C1q/p14ARF Axis

Temporomandibular joint osteoarthritis (TMJ-OA) is a progressive degenerative disorder, for which therapeutic interventions remain limited. The disruption of metabolic homeostasis plays a critical role in the pathogenesis and advancement of TMJ-OA. However, it remains unclear whether extracellular vesicles (EVs) as cellular metabolites are correlated with the pathogenesis, treatment and diagnosis of TMJ-OA. In this study, we demonstrated that autologous circulating extracellular vesicles (C-EVs) possessed significant therapeutic potential for TMJ-OA through the targeted removal of senescent chondrocytes. In a randomized clinical trial (ChiCTR2200063153), C-EV administration was found to significantly enhance condylar bone regeneration and alleviate symptoms relative to hyaluronic acid controls, without eliciting any adverse effects. Comparative analysis revealed that joint cavity-derived EVs from TMJ-OA patients (OA-EVs) exhibited structural abnormalities, diminished expression of canonical EV markers, and pro-inflammatory characteristics. In contrast, C-EVs were significantly enriched with functional proteins C1q binding protein (C1QBP). And the level of C1QBP-positive EVs was positively correlated with therapeutic outcomes, thereby establishing C1QBP as a potential predictive biomarker for TMJ-OA. Furthermore, C-EVs reestablished joint homeostasis by regulating the immune microenvironment and tissue regeneration capacity. Mechanistically, C1QBP^high C-EVs upregulated the expression of membrane C1q on senescent chondrocytes, thereby initiating C1q-C1QBP binding, p14ARF translocation to mitochondria, and subsequent cytochrome C/caspase-3-dependent apoptosis. Our findings demonstrate that C-EVs serve a dual therapeutic role by facilitating the clearance of senescent cells via the C1QBP/C1q/p14ARF axis, while promoting tissue regeneration and regulating metabolites homeostasis, offering a novel biological strategy for TMJ-OA treatment.