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

C-EV administration significantly enhanced condylar bone regeneration and alleviated symptoms in TMJ-OA patients compared to hyaluronic acid controls in a randomized clinical trial.

• The trial was registered as ChiCTR2200063153.
• C-EVs were autologous circulating extracellular vesicles derived from the patients' own circulation.
• No adverse effects were elicited by C-EV administration.
• Hyaluronic acid served as the control treatment.

Joint cavity-derived EVs from TMJ-OA patients (OA-EVs) exhibited structural abnormalities, diminished expression of canonical EV markers, and pro-inflammatory characteristics compared to C-EVs.

• OA-EVs were derived from the joint cavity of TMJ-OA patients.
• OA-EVs showed diminished expression of canonical EV markers.
• OA-EVs displayed pro-inflammatory characteristics.
• Structural abnormalities were observed in OA-EVs by comparative analysis.

C-EVs were significantly enriched with the functional protein C1q binding protein (C1QBP), and the level of C1QBP-positive EVs was positively correlated with therapeutic outcomes.

• C1QBP enrichment in C-EVs was identified through comparative protein analysis.
• The level of C1QBP-positive EVs positively correlated with therapeutic outcomes in TMJ-OA patients.
• C1QBP was established as a potential predictive biomarker for TMJ-OA.
• C1QBPhigh C-EVs were identified as the therapeutically active subpopulation.

C1QBPhigh C-EVs eliminated senescent chondrocytes by upregulating membrane C1q expression, initiating C1q-C1QBP binding, p14ARF translocation to mitochondria, and subsequent cytochrome C/caspase-3-dependent apoptosis.

• The mechanistic axis identified was C1QBP/C1q/p14ARF.
• C-EVs upregulated membrane C1q expression on senescent chondrocytes.
• C1q-C1QBP binding triggered p14ARF translocation to mitochondria.
• Mitochondrial p14ARF translocation led to cytochrome C release and caspase-3-dependent apoptosis.
• This mechanism specifically targeted senescent chondrocytes for clearance.

C-EVs reestablished joint homeostasis by regulating the immune microenvironment and tissue regeneration capacity.

• C-EVs served a dual therapeutic role: clearance of senescent cells and promotion of tissue regeneration.
• C-EVs regulated metabolite homeostasis in the joint.
• Regulation of the immune microenvironment was identified as a mechanism of C-EV action.
• C-EVs are described as cellular metabolites whose disruption is linked to TMJ-OA pathogenesis.

Disruption of metabolic homeostasis plays a critical role in the pathogenesis and advancement of TMJ-OA.

• TMJ-OA is described as a progressive degenerative disorder with limited therapeutic interventions.
• Extracellular vesicles are characterized as cellular metabolites correlated with TMJ-OA pathogenesis, treatment, and diagnosis.
• The study examined whether EVs are correlated with the pathogenesis, treatment, and diagnosis of TMJ-OA.