SEMA6D modulates extracellular matrix metabolism in osteoarthritis by inhibiting the AGT / AGTR1a / IL ‐1β axis

Abstract The tissue‐localized renin‐angiotensin system (tRAS) plays a pivotal role in the crosstalk between cardiovascular factors and osteoarthritis (OA). Semaphorin 6D (SEMA6D), a cardiovascular neuroeffector, may contribute to chondrocyte homeostasis; however, its cartilage‐specific functions remain unclear. Chondrocytes with altered SEMA6D expression were established via gene transfection. RNA sequencing was performed to identify SEMA6D‐related genes and pathways, with preliminary validation in human OA samples. Furthermore, biochemical methods were employed to investigate the role of the AGT/AGTR1a/IL‐1β axis in mediating SEMA6D‐associated extracellular matrix metabolism (ECM). An AAV5‐based lentiviral vector was used to generate OA rat models overexpressing SEMA6D, followed by radiological and histological analyses. SEMA6D overexpression significantly enhanced ECM homeostasis, marked by increased Aggrecan, COL2A1 and decreased COL10A1, MMP13, and Runx2 expression. These SEMA6D‐induced genes were enriched in the tRAS pathway, with AGT, AGTR1a, and IL‐1β identified as critical targets. Furthermore, the AGT/AGTR1a/IL‐1β axis activated ECM degradation in chondrocytes, while SEMA6D overexpression effectively suppressed this signaling. In the OA rat model, elevated SEMA6D expression significantly reduced cartilage degradation. SEMA6D confers chondroprotective effects in OA by modulating the tRAS pathway, likely through inhibition of the AGT/AGTR1a/IL‐1β axis, thereby regulating ECM metabolism and chondrocyte hypertrophy. These findings enhance our understanding of cardiovascular influences on cartilage health and reveal tissue‐specific regulatory mechanisms in OA.