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Bone. 2018 Dec;117:149-160. doi: 10.1016/j.bone.2018.09.008. Epub 2018 Sep 13.

Demethylation of ITGAV accelerates osteogenic differentiation in a blast-induced heterotopic ossification in vitro cell culture model.

Author information

1
Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom,. Electronic address: n.logan@imperial.ac.uk.
2
Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom.
3
Farjo Hair Institute, London, W1G 7LH, United Kingdom. Electronic address: dr.greg@farjo.com.
4
Department of Bioengineering, Imperial College London, London SW7 2AZ, United Kingdom,. Electronic address: c.higgins@imperial.ac.uk.

Abstract

Trauma-induced heterotopic ossification is an intriguing phenomenon involving the inappropriate ossification of soft tissues within the body such as the muscle and ligaments. This inappropriate formation of bone is highly prevalent in those affected by blast injuries. Here, we developed a simplified cell culture model to evaluate the molecular events involved in heterotopic ossification onset that arise from the shock wave component of the disease. We exposed three subtypes of human mesenchymal cells in vitro to a single, high-energy shock wave and observed increased transcription in the osteogenic master regulators, Runx2 and Dlx5, and significantly accelerated cell mineralisation. Reduced representation bisulfite sequencing revealed that the shock wave altered methylation of gene promoters, leading to opposing changes in gene expression. Using a drug to target ITGAV, whose expression was perturbed by the shock wave, we found that we could abrogate the deposition of mineral in our model. These findings show how new therapeutics for the treatment of heterotopic ossification can be identified using cell culture models.

KEYWORDS:

Blast overpressure exposure; Epigenetic DNA methylation; Heterotopic ossification; In vitro model; Ossification

PMID:
30219480
PMCID:
PMC6218666
DOI:
10.1016/j.bone.2018.09.008
[Indexed for MEDLINE]
Free PMC Article

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