Identifying fibroblast growth factor receptor 3 as a mediator of periosteal osteochondral differentiation through the construction of microRNA-based interaction networks

Article

Wells, L., Roberts, H., Luyten, F. and Roberts, S. 2023. Identifying fibroblast growth factor receptor 3 as a mediator of periosteal osteochondral differentiation through the construction of microRNA-based interaction networks. Biology. 12 (11). https://doi.org/10.3390/biology12111381
TypeArticle
TitleIdentifying fibroblast growth factor receptor 3 as a mediator of periosteal osteochondral differentiation through the construction of microRNA-based interaction networks
AuthorsWells, L., Roberts, H., Luyten, F. and Roberts, S.
Abstract

Human periosteum-derived progenitor cells (hPDCs) have the ability to differentiate towards both the chondrogenic and osteogenic lineages. This coordinated and complex osteochondrogenic differentiation process permits endochondral ossification and is essential in bone development and repair. We have previously shown that humanised cultures of hPDCs enhance their osteochondrogenic potentials in vitro and in vivo; however, the underlying mechanisms are largely unknown. This study aimed to identify novel regulators of hPDC osteochondrogenic differentiation through the construction of miRNA-mRNA regulatory networks derived from hPDCs cultured in human serum or foetal bovine serum as an alternative in silico strategy to serum characterisation. Sixteen differentially expressed miRNAs (DEMis) were identified in the humanised culture. In silico analysis of the DEMis with TargetScan allowed for the identification of 1503 potential miRNA target genes. Upon comparison with a paired RNAseq dataset, a 4.5% overlap was observed (122 genes). A protein–protein interaction network created with STRING interestingly identified FGFR3 as a key network node, which was further predicted using multiple pathway analyses. Functional analysis revealed that hPDCs with the activating mutation FGFR3N540K displayed increased expressions of chondrogenic gene markers when cultured under chondrogenic conditions in vitro and displayed enhanced endochondral bone formation in vivo. A further histological analysis uncovered known downstream mediators involved in FGFR3 signalling and endochondral ossification to be upregulated in hPDC FGFR3N540K-seeded implants. This combinational approach of miRNA-mRNA-protein network analysis with in vitro and in vivo characterisation has permitted the identification of FGFR3 as a novel mediator of hPDC biology. Furthermore, this miRNA-based workflow may also allow for the identification of drug targets, which may be of relevance in instances of delayed fracture repair.

KeywordsmicroRNA; osteochondral differentiation; fracture repair; osteoarthritis
Sustainable Development Goals3 Good health and well-being
Middlesex University ThemeHealth & Wellbeing
PublisherMDPI
JournalBiology
ISSN
Electronic2079-7737
Publication dates
Online28 Oct 2023
PrintNov 2023
Publication process dates
Submitted24 Aug 2023
Accepted24 Oct 2023
Deposited24 Nov 2023
Output statusPublished
Publisher's version
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File Access Level
Open
Copyright Statement

Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/)

Digital Object Identifier (DOI)https://doi.org/10.3390/biology12111381
PubMed ID37997980
PubMed Central ID10669632
Web of Science identifierWOS:001107831300001
MEDLINE:37997980
National Library of Medicine ID101587988
LanguageEnglish
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