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Identification of stiffness-induced signalling mechanisms in cells from patent and fused sutures associated with craniosynostosis.

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posted on 22.11.2019 by Sara Barreto, Arlyng Gonzalez Vazquez, Andrew R. Cameron, Fergal J. O'Brien, Dylan J Murray

Craniosynostosis is a bone developmental disease where premature ossification of the cranial sutures occurs leading to fused sutures. While biomechanical forces have been implicated in craniosynostosis, evidence of the effect of microenvironmental stiffness changes in the osteogenic commitment of cells from the sutures is lacking. Our aim was to identify the differential genetic expression and osteogenic capability between cells from patent and fused sutures of children with craniosynostosis and whether these differences are driven by changes in the stiffness of the microenvironment. Cells from both sutures demonstrated enhanced mineralisation with increasing substrate stiffness showing that stiffness is a stimulus capable of triggering the accelerated osteogenic commitment of the cells from patent to fused stages. The differences in the mechanoresponse of these cells were further investigated with a PCR array showing stiffness-dependent upregulation of genes mediating growth and bone development (TSHZ2, IGF1), involved in the breakdown of extracellular matrix (MMP9), mediating the activation of inflammation (IL1β) and controlling osteogenic differentiation (WIF1, BMP6, NOX1) in cells from fused sutures. In summary, this study indicates that stiffer substrates lead to greater osteogenic commitment and accelerated bone formation, suggesting that stiffening of the extracellular environment may trigger the premature ossification of the sutures.

Funding

This work was funded in part by the Irish Research Council Postdoctoral Fellowships (GOIPD/2014/483 and GOIPD/2013/269), by the European Research Council (ERC) under the European Community’s seventh framework programme (FP7/2007–2013/239685), by the Health Research Board under the Health Research Awards - Patient-Oriented Research scheme (HRA-POR-2014-569), by the Temple Street, Children’s Fund for Health (RPAC-2013-06) and by the commercialisation fund of the Enterprise Ireland (CF20144003).

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This article is also available at https://www.nature.com/articles/s41598-017-11801-0#Ack1

Published Citation

Barreto S, González-Vázquez A, Cameron AR, O’Brien FJ, Murray DJ. Identification of stiffness-induced signalling mechanisms in cells from patent and fused sutures associated with craniosynostosis. Scientific Reports. 2017; 7:11494

Publication Date

13/09/2017

Publisher

Nature Publishing Group

PubMed ID

28904366

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