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

被引:0
作者
Patel, Krutik [1 ]
Barter, Matt [2 ]
Soul, Jamie [2 ,3 ]
Clark, Peter [1 ]
Proctor, Carole [1 ]
Clark, Ian [4 ]
Young, David [2 ]
Shanley, Daryl P. [1 ]
机构
[1] Newcastle Univ, Biosci Inst, Campus Ageing & Vital, Newcastle Upon Tyne, England
[2] Newcastle Univ, Regenerat Med Stem Cells Transplantat Biosci Inst, Newcastle Upon Tyne, England
[3] Univ Liverpool, Fac Hlth & Life Sci, Computat Biol Facil, Liverpool, England
[4] Univ East Anglia, Sch Biol Sci, Norwich, England
来源
ELIFE | 2024年 / 12卷
基金
英国医学研究理事会;
关键词
microRNA; chondrogenesis; systems biology; bioinformatics; kinetic modelling; osteoarthritis; STEM-CELL CHONDROGENESIS; EXTRACELLULAR-MATRIX; ACTIN ORGANIZATION; OSTEOARTHRITIS; EXPRESSION; DIFFERENTIATION; CHONDROCYTES; PROGRESSION; MICRORNAS; GROWTH;
D O I
10.7554/eLife.89701
中图分类号
Q [生物科学];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 FZD6, ITGA3 and CAV1 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.
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页数:19
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