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

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

doi:10.3390/ijms23062957

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.

Highlights

Bone is a metabolically active and dynamic organ that remodels throughout life by coordinated activities of bone-resorbing osteoclasts and bone-forming osteoblasts
Previous initial transcriptome analysis compared gene expression in male human bone biopsy samples taken from lumbar spine (LS) and iliac bone (IB) sites that experience high and low levels of mechanical stress, respectively [2]
The present study shows that the degree of DNA methylation differs markedly between mechanically stressed LS and unstressed IB

Summary

Introduction

Bone is a metabolically active and dynamic organ that remodels throughout life by coordinated activities of bone-resorbing osteoclasts and bone-forming osteoblasts. Mechanical loading plays an important role in the maintenance of bone density, but knowledge of the cellular and molecular biology of mechanosensing remains limited. Mature bone is removed by remodeling that occurs as an adaptive response to different factors, including mechanical loading and replacement of damaged bone following micro- and macrofractures. Studies [1,2] have uncovered the initial molecular mechanisms of ZIC1 osteocyte actions and implicated a role in human bone pathophysiology. ZIC1 had been related to craniofacial developmental defects [3]. Its function was further assessed in a large-scale GWAS meta-analysis focusing on BMD variation in the skull, finding

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