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

β受体阻滞剂预防骨质流失的分子和细胞机制

• 批准号: 10767459
• 负责人: CHRISTINE Woods Lary
• 金额: $ 42.58万
• 依托单位: MAINEHEALTH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10767459
• 关键词: ADRB1 gene; Acute; Address; Adrenergic Receptor; Adrenergic beta-Antagonists; Atenolol; Binding; Bone Density; Bone Resorption; CRISPR/Cas technology; Cells; Clinical; Clinical Trials; Competitive Binding; Data; Development; Femur; Funding; Future; Genes; Genetic; Genotype; Goals; Grant; HDAC4 gene; Health; Heterogeneity; Hormone replacement therapy; Human; Individual; Link; Measures; Mediating; MicroRNAs; Modeling; Modification; Molecular; Mus; Neck; Norepinephrine; Observational Study; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis prevention; Outcome; Participant; Pathway interactions; Peripheral Blood Mononuclear Cell; Pharmacogenetics; Postmenopausal Osteoporosis; Postmenopause; Prevention; Prevention strategy; Randomized, Controlled Trials; Receptor Signaling; Risk; Safety; Sampling; Signal Pathway; Signal Transduction; Source; Testing; Variant; Viral; Woman; Women' s Health; beta-2 Adrenergic Receptors; bone; bone health; bone loss; circulating microRNA; drug discovery; efficacy evaluation; fracture risk; genetic variant; genome-wide; improved; in vivo; knock-down; mRNA Expression; novel; novel therapeutics; overexpression; personalized medicine; treatment effect; treatment group; treatment response; treatment strategy

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.

摘要/概要 绝经后骨质流失一直是一个悬而未决的临床问题，因为妇女的健康倡议 激素替代疗法的风险为了解决这个问题，一项使用β受体阻滞剂的临床试验 (BBs)改善骨骼健康的研究最近得到了资助，题为“β 1选择性阻断预防骨质疏松症”。 绝经后骨质流失：一项随机对照试验”（R 01 AG 065154-A1）。虽然这项试验将评估 BB用于该适应症的有效性和安全性，仍将存在关于机制和最佳使用的问题。 这一预防策略。已经观察到BB对骨结局的影响具有异质性，这可能是由于 药物遗传学，因为我们已经发现并验证了ADRB 1和HDAC 4中的药物遗传学变体。 此外，治疗效果的机制仍然存在争议。尽管之前的小鼠研究 表明BB的有益骨效应是由于与B2-肾上腺素能受体的竞争性结合 （B2-AR）对成骨细胞的作用，许多人体研究发现B1选择性阻断剂与更好的成骨细胞相关。 骨结果。此外，我们发现miR-19 a-3 p，我们假设它靶向B1-AR， （ADRB 1）与BB使用和较高的骨矿物质密度（BMD）相关。我们还展示了 在ADRB 1变异体中存在药物遗传学关联，其与miR-19 a-3 p表达正相关。 在小鼠研究中，我们已经显示了BB治疗对破骨细胞的一种新的直接作用， 成骨细胞信号传导。总之，我们的初步药物遗传学和微小RNA结果强调了 除了B2-AR信号外，B1-AR对BB骨效应的重要性，我们的小鼠研究显示了证据， BB处理对破骨细胞的直接影响以及通过成骨细胞的间接影响。我们的中央 假设是与治疗反应相关的遗传和microRNA（miRNA）变量有助于 成骨细胞和破骨细胞中B1-AR和B2-AR信号通路的调节。我们将测试这个 1）测量体内阿替洛尔治疗对分化的影响 在参与者衍生破骨细胞中，发现并验证阿替洛尔治疗的药物遗传学变体 反应，并表征其对成骨细胞和破骨细胞的功能作用。2)使用miRNA-seq 鉴定与治疗反应相关的循环miRNA，并发现靶点和验证机制 在成骨细胞和破骨细胞中。我们建议严格执行这些目标使用参与者衍生的样本 从前面提到的审判。这一建议将使我们能够表征BB治疗的机制 对绝经后妇女骨的影响，并建立个性化的治疗模式。