Inhibition of Fibroblast Activation Protein‐α Ameliorates Intervertebral Disc Degeneration via Reduced Vascular Invasion in Cartilage Endplate

Intervertebral disc degeneration (IDD) is a primary cause of low back pain, with the development of new blood vessels being a key pathological feature. Fibroblast activation protein-alpha (FAP-α), a member of the Type II serine protease family, possesses dipeptidase and collagenase activities and is closely linked to angiogenesis. Bioinformatics and immunohistochemical analysis revealed elevated FAP-α expression and increased angiogenesis in degenerated cartilage endplate (CEP). Co-culture of FAP-α-silenced CEP cells or conditioned media with human umbilical vein endothelial cells (HUVECs) demonstrated a reduction in hypoxia-inducible factor-α (HIF-α) levels, vascular endothelial growth factor (VEGF)-A and PI3K/AKT phosphorylation, which impaired HUVEC migration and tube formation. Conversely, FAP-α overexpression enhanced angiogenesis via the PI3K/AKT/HIF-α/VEGF-A signalling pathway. In rats with IDD induced by lumbar instability, FAP-α inhibitors reduced angiogenesis and ossification of the CEP, thereby delaying IDD progression associated with CEP degeneration. Genetic deletion of FAP further slowed IDD progression. Collectively, these findings provide compelling evidence that FAP-α accelerates IDD by promoting angiogenesis, which disrupts disc homeostasis. Targeting FAP-α may offer a novel therapeutic approach for mitigating IDD.