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

## TL;DR

Elevated methylmalonic acid in aging discs causes spinal degeneration by promoting blood vessel growth, and blocking this process with lenvatinib may offer a new treatment.

## Contribution

Identifies methylmalonic acid as a novel aging-related driver of disc degeneration via CCL7/JAK2-STAT3/VEGF signaling and validates lenvatinib as a potential therapy.

## Key findings

- Methylmalonic acid levels are elevated in elderly intervertebral discs and correlate with degeneration.
- Methylmalonic acid induces disc vascularization through the CCL7/JAK2-STAT3/VEGF signaling pathway.
- Lenvatinib, a VEGF receptor inhibitor, delays disc degeneration in mouse models.

## Abstract

Intervertebral disc degeneration (IVDD) is an age‐related degenerative spinal disorder, with age as the primary independent risk factor. To investigate the key pathogenic mechanisms of IVDD, we conducted biochemical analyses on IVD specimens from elderly and young groups. In this study, we found that methylmalonic acid (MMA) levels are significantly elevated within the discs of the elderly group, suggesting that MMA may be a critical metabolite involved in aging‐induced IVDD. In in vitro experiments, we observed that MMA treatment of nucleus pulposus cells (NPCs) upregulated the expression of extracellular matrix catabolic markers and downregulated the expression of anabolic markers. Further validation in an in vivo mouse model of needle puncture‐induced IVDD confirmed that MMA accelerates IVDD progression. Mechanistically, we demonstrated that MMA upregulates the expression of C‐C motif chemokine ligand 7 (CCL7) in NPCs. CCL7 acts as a chemoattractant, further enhancing Janus kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) signaling transduction, ultimately leading to upregulated vascular endothelial growth factor (VEGF) expression. This promotes abnormal growth of vascular endothelial cells, resulting in disc vascularization. Additional in vivo and in vitro experiments confirmed that disc vascularization is a key progression factor in IVDD. As a rescue strategy, we administered lenvatinib, a VEGF receptor inhibitor, which delayed IVDD progression. Therefore, VEGF and disc vascularization represent a promising therapeutic target for IVDD, offering an innovative approach to addressing IVDD treatment in clinical practice.

Our study reveals that elevated MMA in aged intervertebral discs promotes degeneration by activating the CCL7/JAK2‐STAT3/VEGF signaling axis, which drives pathological vascularization. Therapeutically, the VEGFR inhibitor lenvatinib attenuated this process, identifying disc vascularization as a promising therapeutic target for IVDD.