SERPINA3 is a marker of cartilage differentiation and is essential for the expression of extracellular matrix genes during early chondrogenesis.

Autor: Barter MJ; Skeletal Research Group, Biosciences Institute, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK., Turner DA; Institute of Life Course and Medical Sciences, Faculty of Health and Life Sciences, University of Liverpool, William Henry Duncan Building, 6 West Derby St, Liverpool L7 8TX, UK., Rice SJ; Skeletal Research Group, Biosciences Institute, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK., Hines M; Institute of Life Course and Medical Sciences, Faculty of Health and Life Sciences, University of Liverpool, William Henry Duncan Building, 6 West Derby St, Liverpool L7 8TX, UK., Lin H; Skeletal Research Group, Biosciences Institute, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK., Falconer AMD; Skeletal Research Group, Biosciences Institute, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK., McDonnell E; Computational Biology Facility, University of Liverpool, MerseyBio, Crown Street, Liverpool L69 7ZB, UK., Soul J; Skeletal Research Group, Biosciences Institute, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK; Computational Biology Facility, University of Liverpool, MerseyBio, Crown Street, Liverpool L69 7ZB, UK., Arques MDC; Skeletal Research Group, Biosciences Institute, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK., Europe-Finner GN; Skeletal Research Group, Biosciences Institute, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK., Rowan AD; Skeletal Research Group, Biosciences Institute, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK., Young DA; Skeletal Research Group, Biosciences Institute, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK., Wilkinson DJ; Skeletal Research Group, Biosciences Institute, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK; Institute of Life Course and Medical Sciences, Faculty of Health and Life Sciences, University of Liverpool, William Henry Duncan Building, 6 West Derby St, Liverpool L7 8TX, UK. Electronic address: david.wilkinson@liverpool.ac.uk.
Jazyk: angličtina
Zdroj: Matrix biology : journal of the International Society for Matrix Biology [Matrix Biol] 2024 Nov; Vol. 133, pp. 33-42. Date of Electronic Publication: 2024 Aug 02.
DOI: 10.1016/j.matbio.2024.07.004
Abstrakt: Serine 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.
Competing Interests: Declaration of compting interest The authors declare no conflicts of interest.
(Copyright © 2024. Published by Elsevier B.V.)
Databáze: MEDLINE
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