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

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 with 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 subnetwork 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 with 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). Because 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. © 2020 American Society for Bone and Mineral Research (ASBMR).

Pharmacogenomic Effects of β-Blocker Use on Femoral Neck Bone Mineral Density

“…We then determined if the associated miRNAs had been previously associated with osteoporosis or BMD measures, which we term “ bone-related miRNAs ” (Supplementary Table S4; http://clary.mmcri.cloud/JES_Nevola_et_all_supplement.pdf ) [ 36-38 , 76-93 ]. We also noted the association of SNVs with miR-19a-3p and miR-186-5p because we have previously found these to be associated with BB use and BMD [ 31 ]. Finally, we determined if any of the significant miRNAs targeted the gene in which the associated SNV is located in or nearby.…”

“…S3A and S3B; http://clary.mmcri.cloud/JES_Nevola_et_all_supplement.pdf ). We have previously found miR-19a-3p to be positively associated with BB use, total femur BMD, and lumbar spine BMD [ 31 ]. ADRB1 is also a validated target of miR-19a-3p [ 94 ].…”

“…Whole blood from fasting morning samples was used for miRNA profiling, which was obtained at exam 8, coincident with the BB use ascertainment, and just before BMD measurement and stored at –80 °C. Several studies have used these miRNA data in association with BMD, BB use, and other phenotypes [ 31 , 35 , 59 , 60 ]. In brief, the high-throughput Gene Expression Core Laboratory at the University of Massachusetts Medical School profiled commercially available TaqMan miRNA assays [ 35 , 59 , 60 ].…”

“…In addition to genetic variations, we have previously found circulating microRNAs (miRNAs) to be associated with BB use and BMD and revealed potential miRNA-mediated mechanisms by which BB use influences BMD, including attenuation of adrenergic signaling in osteoblasts [ 31 ]. miRNAs are small (~ 22 nucleotides), noncoding RNAs that act on target messenger RNAs (mRNAs) to inhibit protein expression through mRNA degradation and translational inhibition [ 32 ].…”

Regulation of bone metabolism mediated by β-adrenergic receptor and its clinical application

“…Toulis et al [ 33 ] found that BBs, especially selective BBs, was associated with a reduced risk of fracture in men and women, which is consistent with the results of Yang et al [ 31 ]. A study reported that participants who did not use a BB had a lower bone density than those who did not use it, and the difference was equivalent to about 4.5 years of bone loss[ 34 ]. In contrast, some studies have shown that BBs had no significant effect on bone formation and bone density increase.…”