Methylmalonic Acid, an Aging-Associated Metabolite, Accelerates Intervertebral Disc Degeneration by Inducing Disc Vascularization via the CCL7/JAK2-STAT3/VEGF Signaling Axis.

MMA levels are significantly elevated within intervertebral discs of elderly compared to young individuals.

• Biochemical analyses were conducted on IVD specimens from elderly and young groups.
• Elevated MMA was identified as a critical metabolite potentially involved in aging-induced IVDD.
• This finding motivated the investigation of MMA as a key pathogenic mechanism in IVDD.

MMA treatment of nucleus pulposus cells (NPCs) upregulated extracellular matrix catabolic markers and downregulated anabolic markers in vitro.

• In vitro experiments used MMA treatment applied directly to NPCs.
• Catabolic markers of extracellular matrix were upregulated following MMA treatment.
• Anabolic markers of extracellular matrix were downregulated following MMA treatment.
• These findings indicate MMA promotes a degenerative phenotype in disc cells.

MMA accelerates IVDD progression in an in vivo mouse model of needle puncture-induced IVDD.

• A needle puncture-induced IVDD mouse model was used for in vivo validation.
• MMA administration confirmed acceleration of IVDD progression in vivo.
• These results corroborated the in vitro findings regarding MMA's degenerative effects.

MMA upregulates CCL7 expression in NPCs, which acts as a chemoattractant to enhance JAK2/STAT3 signaling and ultimately upregulate VEGF expression.

• MMA mechanistically induces upregulation of C-C motif chemokine ligand 7 (CCL7) in NPCs.
• CCL7 functions as a chemoattractant that further enhances Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling transduction.
• Downstream JAK2/STAT3 activation leads to upregulated vascular endothelial growth factor (VEGF) expression.
• The complete axis identified is CCL7/JAK2-STAT3/VEGF.

VEGF upregulation promotes abnormal growth of vascular endothelial cells, resulting in disc vascularization.

• Elevated VEGF expression was associated with abnormal proliferation or growth of vascular endothelial cells.
• This process leads to pathological disc vascularization.
• Additional in vivo and in vitro experiments confirmed that disc vascularization is a key progression factor in IVDD.

Lenvatinib, a VEGF receptor inhibitor, delayed IVDD progression as a rescue strategy.

• Lenvatinib was administered as a therapeutic intervention targeting the VEGF pathway.
• Lenvatinib treatment delayed progression of IVDD in the experimental model.
• VEGF and disc vascularization are identified as promising therapeutic targets for IVDD.
• The authors describe this as 'an innovative approach to addressing IVDD treatment in clinical practice.'