Systems analysis of miR-199a/b-5p and multiple miR-199a/b-5p targets during chondrogenesis

Changes in chondrocyte gene expression can contribute to the development of osteoarthritis (OA), and so recognition of the regulative processes during chondrogenesis can lead to a better understanding of OA. microRNAs (miRNAs) are key regulators of gene expression in chondrocytes/OA, and we have use...

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Bibliographic Details
Published in:eLife 2024-10, Vol.12
Main Authors: Patel, Krutik, Barter, Matt, Soul, Jamie, Clark, Peter, Proctor, Carole, Clark, Ian, Young, David, Shanley, Daryl P
Format: Article
Language:English
Subjects:
bioinformatics
Biomarkers
Calcium channels (voltage-gated)
Cartilage
Chondrocytes
Chondrocytes - metabolism
Chondrogenesis
Chondrogenesis - genetics
Chromosome 5
Computational and Systems Biology
Computational Biology - methods
Epidermal growth factor
Extracellular matrix
Gene expression
Gene Expression Regulation
Humans
kinetic modelling
microRNA
MicroRNAs
MicroRNAs - genetics
MicroRNAs - metabolism
miRNA
Osteoarthritis
Osteoarthritis - genetics
Osteoarthritis - metabolism
Stem cells
systems biology
Vascular endothelial growth factor
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Summary:Changes in chondrocyte gene expression can contribute to the development of osteoarthritis (OA), and so recognition of the regulative processes during chondrogenesis can lead to a better understanding of OA. microRNAs (miRNAs) are key regulators of gene expression in chondrocytes/OA, and we have used a combined experimental, bioinformatic, and systems biology approach to explore the multiple miRNA-mRNA interactions that regulate chondrogenesis. A longitudinal chondrogenesis bioinformatic analysis identified paralogues miR-199a-5p and miR-199b-5p as pro-chondrogenic regulators. Experimental work in human cells demonstrated alteration of miR-199a-5p or miR-199b-5p expression led to significant inverse modulation of key chondrogenic genes and extracellular matrix production. miR-199a/b-5p targets and were identified by inhibition experiments and verified as direct targets by luciferase assay. The experimental work was used to generate and parameterise a multi-miRNA 14-day chondrogenesis kinetic model to be used as a repository for the experimental work and as a resource for further investigation of this system. This is the first multi-miRNA model of a chondrogenesis-based system, and highlights the complex relationships between regulatory miRNAs, and their target mRNAs.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.89701