Title

miRNA Mechanisms Underlying the Association of Beta Blocker Use and Bone Mineral Density.

Document Type

Article

Publication Date

8-12-2020

Institution/Department

Center for Molecular Medicine, Center for Outcomes Research and Evaluation, Maine Medical Center Research Institute

Journal Title

Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

MeSH Headings

Absorptiometry, Photon, Bone Density, MicroRNAs, Adrenergic beta-Antagonists

Abstract

Osteoporosis is a debilitating and costly disease that causes fractures in 33% of women and 20% of men over the age of 50 years. Recent studies have shown that beta blocker (BB) users have higher bone mineral density (BMD) and decreased risk of fracture compared to non-users. The mechanism underlying this association is thought to be due to suppression of adrenergic signaling in osteoblasts, which leads to increased BMD in rodent models; however the mechanism in humans is unknown. Also, several miRNAs are associated with adrenergic signaling and BMD in separate studies. To investigate potential miRNA mechanisms, we performed a cross-sectional analysis using clinical data, dual-energy X-ray absorptiometry (DXA) scans, and miRNA and mRNA profiling of whole blood from the Framingham Study's Offspring Cohort. We found nine miRNAs associated with BB use and increased BMD. In parallel network analyses we discovered a sub-network associated with BMD and BB use containing two of these nine miRNAs, miR-19a-3p and miR-186-5p. To strengthen this finding, we showed that these two miRNAs had significantly higher expression in individuals without incident fracture compared to those with fracture in an external data set. We also noted a similar trend in association between these miRNA and Z-score as calculated from heel ultrasound measures in two external cohorts (SOS-Hip and SHIP-TREND). Since miR-19a directly targets the ADRB1 mRNA transcript, we propose BB use may downregulate ADRB1 expression in osteoblasts through increased miR-19a-3p expression. We used enrichment analysis of miRNA targets to find potential indirect effects through insulin and parathyroid hormone signaling. This analysis provides a starting point for delineating the role of miRNA on the association between BB use and BMD. This article is protected by copyright. All rights reserved.

ISSN

1523-4681

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