A Core Omnigenic Non-coding Trait Governing Dex-Induced Osteoporotic Effects Identified Without DEXA

Li Lu; Yanzhen Cai; Xiaoling Luo; Zhangting Wang; Sin Hang Fung; Huanhuan Jia; Chi Lam Yu; Wai Yee Chan; Kai Kei Miu; Wende Xiao

doi:10.3389/fphar.2021.750959

A Core Omnigenic Non-coding Trait Governing Dex-Induced Osteoporotic Effects Identified Without DEXA

Front Pharmacol. 2021 Nov 24:12:750959. doi: 10.3389/fphar.2021.750959. eCollection 2021.

Authors

Li Lu¹, Yanzhen Cai¹, Xiaoling Luo¹, Zhangting Wang², Sin Hang Fung², Huanhuan Jia^{1

3}, Chi Lam Yu², Wai Yee Chan², Kai Kei Miu², Wende Xiao⁴

Affiliations

¹ Guangdong Key Laboratory of Pharmaceutical Bioactive Substances, School of Life Science and Biopharmacy, Guangdong Pharmaceutical University, Guangzhou, China.
² School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, SAR China.
³ Guangdong Key Laboratory of Laboratory Animals, Guangdong Laboratory Animals Monitoring Institute, Guangzhou, China.
⁴ Department of Orthopedics, Guangzhou First People's Hospital, School of Medicine, South China University of Technology, Guangzhou, China.

Abstract

Iatrogenic glucocorticoid (GC)-induced osteoporosis (GIO) is an idiosyncratic form of secondary osteoporosis. Genetic predisposition among individuals may give rise to variant degree of phenotypic changes but there has yet been a documented unified pathway to explain the idiosyncrasy. In this study, we argue that the susceptibility to epigenetic changes governing molecular cross talks along the BMP and PI3K/Akt pathway may underline how genetic background dictate GC-induced bone loss. Concordantly, osteoblasts from BALB/c or C57BL/6 neonatal mice were treated with dexamethasone for transcriptome profiling. Furthermore, we also confirmed that GC-pre-conditioned mesenchymal stem cells (MSCs) would give rise to defective osteogenesis by instigating epigenetic changes which affected the accessibility of enhancer marks. In line with these epigenetic changes, we propose that GC modulates a key regulatory network involving the scavenger receptor Cd36 in osteoblasts pre-conditioning pharmacological idiosyncrasy in GIO.

Keywords: bone loss; bone morphogenetic protein signaling pathway; cis-expression quantitative trait loci; glucocorticoid; glucocorticoid-induced osteoporosis; osteoblasts differentiation.