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Lookup NU author(s): Dr Matthew Barter, Dr Sarah RiceORCiD, Hua Lin, Dr Adrian Falconer, Dr Jamie Soul, Dr Maria Arques Mengual, Emeritus Professor Nick Europe-Finner, Emeritus Professor Drew Rowan, Professor David YoungORCiD, Dr David Wilkinson
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2024Serine proteinase inhibitors (serpins) are a family of structurally similar proteins which regulate many diverse biological processes from blood coagulation to extracellular matrix (ECM) remodelling. Chondrogenesis involves the condensation and differentiation of mesenchymal stem cells (MSCs) into chondrocytes which occurs during early development. Here, and for the first time, we demonstrate that one serpin, SERPINA3 (gene name SERPINA3, protein also known as alpha-1 antichymotrypsin), plays a critical role in chondrogenic differentiation. We observed that SERPINA3 expression was markedly induced at early time points during in vitro chondrogenesis. We examined the expression of SERPINA3 in human cartilage development, identifying significant enrichment of SERPINA3 in developing cartilage compared to total limb, which correlated with well-described markers of cartilage differentiation. When SERPINA3 was silenced using siRNA, cartilage pellets were smaller and contained lower proteoglycan as determined by dimethyl methylene blue assay (DMMB) and safranin-O staining. Consistent with this, RNA sequencing revealed significant downregulation of genes associated with cartilage ECM formation perturbing chondrogenesis. Conversely, SERPINA3 silencing had a negligible effect on the gene expression profile during osteogenesis suggesting the role of SERPINA3 is specific to chondrocyte differentiation. The global effect on cartilage formation led us to investigate the effect of SERPINA3 silencing on the master transcriptional regulator of chondrogenesis, SOX9. Indeed, we observed that SOX9 protein levels were markedly reduced at early time points suggesting a role for SERPINA3 in regulating SOX9 expression and activity. In summary, our data support a non-redundant role for SERPINA3 in enabling chondrogenesis via regulation of SOX9 levels.
Author(s): Barter MJ, Turner DA, Rice SJ, Hines M, Lin H, Falconer AMD, McDonnell E, Soul J, Arques MDC, Europe-Finner GN, Rowan AD, Young DA, Wilkinson DJ
Publication type: Article
Publication status: Published
Journal: Matrix Biology
Year: 2024
Volume: 133
Pages: 33-42
Print publication date: 01/11/2024
Online publication date: 02/08/2024
Acceptance date: 30/07/2024
Date deposited: 27/08/2024
ISSN (print): 0945-053X
ISSN (electronic): 1569-1802
Publisher: Elsevier B.V.
URL: https://doi.org/10.1016/j.matbio.2024.07.004
DOI: 10.1016/j.matbio.2024.07.004
Data Access Statement: RNA-seq data are available from GEO accession (GSE247491 and GSE247528). Code for bioinformatic analysis is available in the link provided in Experimental Procedures.
PubMed id: 39097037
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