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.
Authors
- Neil A. Hanley (ORCID: https://orcid.org/0000-0003-3234-4038)
- Christabel Thembela Dube (ORCID: https://orcid.org/0000-0001-8155-5793)
- Richard D. Unwin (ORCID: https://orcid.org/0000-0001-7955-9111)
- Pauline Baird
- Stephen M. Richardson (ORCID: https://orcid.org/0000-0002-7637-4135)
- Lindsay Birchall
- Sonal Patel (ORCID: https://orcid.org/0000-0003-4107-0497)
- Zihan Wu (ORCID: https://orcid.org/0000-0002-2451-5231)
- Judith A. Hoyland (ORCID: https://orcid.org/0000-0003-4876-5208)
- Anna Tierney (ORCID: https://orcid.org/0000-0002-8968-5717)
- Leo Zeef (ORCID: https://orcid.org/0000-0003-2833-7847)
- Tengyang Qiu (ORCID: https://orcid.org/0000-0002-2087-4843)
- Rachel Jennings (ORCID: https://orcid.org/0000-0003-1492-600X)
- Leslie M. Shaw (ORCID: https://orcid.org/0000-0002-7650-1210)
- Adrian Ionescu (ORCID: https://orcid.org/0000-0002-6111-834X)
Institutions
- University Hospitals Birmingham NHS Foundation Trust (GB)
- King's College London (GB)
- Manchester Academic Health Science Centre (GB)
- Wellcome Centre for Cell-Matrix Research (GB)
- University of Manchester (GB)
- University College Birmingham (GB)
- Manchester University NHS Foundation Trust (GB)
- STMicroelectronics (United Kingdom) (GB)
Publication Details
- Journal
- iScience
- Published
- 2025-12-05
- DOI
- https://doi.org/10.1016/j.isci.2025.114290
- Primary Topic
- Spine and Intervertebral Disc Pathology
- Type
- article
- Field-Weighted Citation Impact
- 0.00