Skip to main content

Research Repository

Advanced Search

Mechanical-Stress-Related Epigenetic Regulation of ZIC1 Transcription Factor in the Etiology of Postmenopausal Osteoporosis

Datta, Harish K.; Kringen, Marianne K.; Tuck, Stephen P.; Salpingidou, Georgia; Olstad, Ole K.; Gautvik, Kaare M.; Cockell, Simon J.; Gautvik, Vigdis T.; Prediger, Michael; Wu, Jun Jie; Birch, Mark A.; Reppe, Sjur

Mechanical-Stress-Related Epigenetic Regulation of ZIC1 Transcription Factor in the Etiology of Postmenopausal Osteoporosis Thumbnail


Authors

Harish K. Datta

Marianne K. Kringen

Stephen P. Tuck

Ole K. Olstad

Kaare M. Gautvik

Simon J. Cockell

Vigdis T. Gautvik

Michael Prediger

Mark A. Birch

Sjur Reppe



Abstract

Mechanical loading exerts a profound influence on bone density and architecture, but the exact mechanism is unknown. Our study shows that expression of the neurological transcriptional factor zinc finger of the cerebellum 1 (ZIC1) is markedly increased in trabecular bone biopsies in the lumbar spine compared with the iliac crest, skeletal sites of high and low mechanical stress, respectively. Human trabecular bone transcriptome analyses revealed a strong association between ZIC1 mRNA levels and gene transcripts characteristically associated with osteoblasts, osteocytes and osteoclasts. This supposition is supported by higher ZIC1 expression in iliac bone biopsies from postmenopausal women with osteoporosis compared with age-matched control subjects, as well as strongly significant inverse correlation between ZIC1 mRNA levels and BMI-adjusted bone mineral density (BMD) (Z-score). ZIC1 promoter methylation was decreased in mechanically loaded vertebral bone compared to unloaded normal iliac bone, and its mRNA levels correlated inversely with ZIC1 promoter methylation, thus linking mechanical stress to epigenetic control of gene expression. The findings were corroborated in cultures of rat osteoblast progenitors and osteoblast-like cells. This study demonstrates for the first time how skeletal epigenetic changes that are affected by mechanical forces give rise to marked alteration in bone cell transcriptional activity and translate to human bone pathophysiology.

Citation

Datta, H. K., Kringen, M. K., Tuck, S. P., Salpingidou, G., Olstad, O. K., Gautvik, K. M., …Reppe, S. (2022). Mechanical-Stress-Related Epigenetic Regulation of ZIC1 Transcription Factor in the Etiology of Postmenopausal Osteoporosis. International Journal of Molecular Sciences, 23(6), Article 2957. https://doi.org/10.3390/ijms23062957

Journal Article Type Article
Acceptance Date Mar 5, 2022
Online Publication Date Mar 9, 2022
Publication Date 2022-03
Deposit Date Jul 6, 2022
Publicly Available Date Jul 6, 2022
Journal International Journal of Molecular Sciences
Print ISSN 1661-6596
Publisher MDPI
Peer Reviewed Peer Reviewed
Volume 23
Issue 6
Article Number 2957
DOI https://doi.org/10.3390/ijms23062957

Files

Published Journal Article (25.2 Mb)
PDF

Publisher Licence URL
http://creativecommons.org/licenses/by/4.0/

Copyright Statement
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited





You might also like



Downloadable Citations