Molecular and cellular mechanisms of prevention of bone loss by beta blockers

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Abstract/Summary Post-menopausal bone loss has been an unresolved clinical problem since the Women’s Health Initiative showed the risks of hormone replacement therapy. To address this issue, a clinical trial using beta blockers (BBs) to improve bone health has recently been funded entitled, “Beta1-selective blockade for prevention of postmenopausal bone loss: A randomized controlled trial” (R01 AG065154-A1). While this trial will evaluate the efficacy and safety of BBs for this indication, questions will remain about the mechanism and optimal use of this prevention strategy. Heterogeneity of BB effects on bone outcomes have been observed and may be due to pharmacogenetics, as we have discovered and validated pharmacogenetic variants in ADRB1 and HDAC4. Furthermore, the mechanisms of treatment effect remain controversial. Although previous mouse studies showed that the beneficial bone effects of BBs were due to competitive binding to B2-adrenergic receptors (B2-ARs) on osteoblasts, many human studies have found B1-selective blockers to be associated with better bone outcomes. In addition, we have discovered that miR-19a-3p, which we hypothesize to target B1-AR (ADRB1), is associated with BB use and higher bone mineral density (BMD). We also show a pharmacogenetic association in an ADRB1 variant, which is positively associated with miR-19a-3p expression. In mouse studies, we have shown a novel direct effect of BB treatment on osteoclasts that is not mediated by osteoblast signaling. In summary, our preliminary pharmacogenetic and microRNA results underscore the importance of B1-AR in addition to B2-AR signaling for BB bone effects, and our mouse studies show evidence of direct effects of BB treatment on osteoclasts in addition to indirect effects via osteoblasts. Our central hypothesis is that genetic and microRNA (miRNA) variables associated with treatment response contribute to modulation of B1-AR and B2-AR signaling pathways in osteoblasts and osteoclasts. We will test this hypothesis via the following specific aims: 1) Measure the effect of in vivo atenolol treatment on differentiation in participant-derived osteoclasts, discover and validate pharmacogenetic variants of atenolol treatment response, and characterize their functional effects on osteoblasts and osteoclasts. 2) Use miRNA-seq to identify circulating miRNAs associated with treatment response, and discover targets and validate mechanisms in osteoblasts and osteoclasts. We propose to rigorously perform these aims using participant-derived samples from the previously mentioned trial. This proposal will allow us to characterize the mechanisms of BB treatment effect on bone in post-menopausal women and to create personalized treatment models.