| Title: |
SOX9 haploinsufficiency reveals SOX9-Noggin interaction in BMP-SMAD signaling pathway in chondrogenesis |
| Authors: |
Ha, Tin-Yan; Chan, See-Wing; Wang, Zhangting; Law, Patrick Wai Nok; Miu, Kai-Kei; Lu, Gang; Chan, Wai-Yee |
| Contributors: |
CUHK VC Discretionary Fund; A-Smart Group; CUHK Laboratory Support Special Fund for Key Laboratory for Regenerative Medicine, Ministry of Education, China; Innovation and Technology Commission; NSFC/RGC Joint Grant; Innovation and Technology Commission grant; Co-funding Mechaism on Joint Laboratories with the CAS |
| Source: |
Cellular and Molecular Life Sciences ; volume 82, issue 1 ; ISSN 1420-9071 |
| Publisher Information: |
Springer Science and Business Media LLC |
| Publication Year: |
2025 |
| Description: |
Campomelic Dysplasia (CD) is a rare congenital disease caused by haploinsufficiency (HI) in SOX9. Patients with CD typically present with skeletal abnormalities and 75% of them have sex reversal. In this study, we use CRISPR/Cas9 to generate a human induced pluripotent stem cell (hiPSC) model from a heathy male donor, based on a previously reported SOX9 splice site mutation in a CD patients. This hiPSCs-derived chondrocytes from heterozygotes (HT) and homozygotes (HM) SOX9 mutation carriers showed significant defects in chondrogenesis. Bulk RNA profiling revealed that the BMP-SMAD signaling pathway, ribosome-related, and chromosome segregation-related gene sets were altered in the HT chondrocytes. The profile also showed significant noggin upregulation in CD chondrocytes, with ChIP-qPCR confirming that SOX9 binds to the distal regulatory element of noggin. This suggests SOX9 plays a feedback role in the BMP signaling pathway by modulating noggin expression rather than acting solely as a downstream regulator. This provides further insights into its dosage sensitivity in chondrogenesis. Overexpression of SOX9 showed promising results with improved sulfated glycosaminoglycans (GAGs) aggregation and COL2A1 expression following differentiation. We hope this finding could provide a better understanding of the dosage-dependent role of SOX9 in chondrogenesis and contribute to the development of improved therapeutic targets for CD patients. |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| DOI: |
10.1007/s00018-025-05622-y |
| DOI: |
10.1007/s00018-025-05622-y.pdf |
| DOI: |
10.1007/s00018-025-05622-y/fulltext.html |
| Availability: |
https://doi.org/10.1007/s00018-025-05622-y; https://link.springer.com/content/pdf/10.1007/s00018-025-05622-y.pdf; https://link.springer.com/article/10.1007/s00018-025-05622-y/fulltext.html |
| Rights: |
https://creativecommons.org/licenses/by/4.0 ; https://creativecommons.org/licenses/by/4.0 |
| Accession Number: |
edsbas.96B6C493 |
| Database: |
BASE |