EVC protein regulates Sonic hedgehog signaling during human intervertebral disc development and degeneration.

Notochord-derived cells (NCs) in the developing nucleus pulposus (NP) of the intervertebral disc maintain its hydrated extracellular matrix and their aging-associated loss initiates intervertebral disc degeneration, contributing to back pain. To better understand the molecular regulators of NC function, we profiled the proteome of human fetal NP cells and identified Ellis-van Creveld (EVC) protein as highly enriched in NCs. Using mouse models and CRISPR-engineered human NP cells, we show that EVC facilitates Shh signaling, supports NP cell phenotype, and limits fibrotic matrix changes. Loss of EVC reduced Gli3 processing, impaired Shh pathway activity, and altered extracellular matrix organization, while TGF-β signaling suppressed EVC expression indicating crosstalk between these pathways. These findings establish EVC as a key modulator of developmental and homeostatic signaling in the disc and suggest potential therapeutic targets for disc degeneration and fibrosis, providing strategies for preserving NP function and informing regenerative approaches.