ABSTRACT 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.
Meng et al. (2026) studied this question.