Glucocorticoid-induced bone loss via Beta2-adrenergic signaling in osteoblasts

糖皮质激素通过成骨细胞中的 Beta2 肾上腺素信号传导诱导骨质流失

• 批准号: 7275682
• 负责人: Florent Elefteriou
• 金额: $ 14.45万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7275682
• 关键词: beta adrenergic receptor; beta antiadrenergic agent; biological signal transduction; chemoprevention; corticosterone; cytoprotection; genetic promoter element; genetic transcription; genetically modified animals; glucocorticoids; isoproterenol; laboratory mouse; osteoblasts; osteoclasts; pathologic bone resorption; physiologic bone resorption; propranolol; skeletal pharmacology; sympathetic nervous system; tissue /cell culture; transfection /expression vector

DESCRIPTION (provided by applicant): Bone remodeling, i.e. the process whereby osteoblasts and osteoclasts renew bone, is controlled by hormones, autocrine/paracrine factors and also by the central and peripheral nervous system. Indeed, we have shown that the adipocyte-derived hormone leptin inhibits bone formation via a hypothalamic relay, and that the signal between hypothalamic neurons and bones is conveyed via the sympathetic nervous system (SNS) and beta2-adrenergic receptors (?2AR) expressed in osteoblasts. In vivo, blocking of ??AR signaling increases bone formation, while stimulating ??AR signaling decreases it. Our long-term goal is to characterize the central and peripheral mechanisms whereby the nervous system controls osteoblast function. This specific application focuses on the regulation of ??AR expression in osteoblasts and its pathophysiological relevance in the context of glucocorticoid-induced bone loss. Glucocorticoids induce bone loss by a poorly characterized and still controversial mechanism of action. Our preliminary results indicate that 1) dexamethasone induces ??AR expression in osteoblasts, 2) the Adr?2 promoter contains GRE-binding sites and 3) isoproterenol, a bAR agonist, exacerbates corticosterone-induced bone loss in WT mice in vivo. In light of these results, we postulate that the mode of action of glucocorticoids requires ??AR signaling in osteoblasts and specifically that glucocorticoids increase ??AR expression and responsiveness to the SNS in osteoblasts, and thereby amplify the antiosteogenic function of the SNS, leading to bone loss. To test this hypothesis, we intend to 1) use ??AR-/- mice to test the effect of corticosterone in mice lacking ??AR signaling, 2) perform in vitro cell signaling and promoter analyses to characterize the effect of glucocorticoid treatment downstream of ??AR and on Adr?2 transcription, and 3) test in vivo the putative protective effect of b-blockers on glucocorticoid-induced bone loss. Lay summary: Glucocorticoids used for the treatment of asthma or arthritis induce bone loss by a poorly understood mechanism. We will test the hypothesis that glucocorticoids exert this action on bone by increasing bone responsiveness to neuronal signals inhibiting bone formation. Identification of such mechanism, if verified, will be an incentive for the use of beta-blockers as a preventive treatment aimed at blocking glucocorticoid-induced bone loss.

描述（由申请人提供）：骨重塑，即成骨细胞和破骨细胞更新骨骼的过程，受到激素、自分泌/旁分泌因子以及中枢和周围神经系统的控制。事实上，我们已经证明，脂肪细胞来源的激素瘦素通过下丘脑中继抑制骨形成，并且下丘脑神经元和骨骼之间的信号是通过交感神经系统（SNS）和β2-肾上腺素能受体（？2AR）传递的。成骨细胞。在体内，阻断 AR 信号传导会增加骨形成，而刺激 AR 信号传导会减少骨形成。我们的长期目标是表征神经系统控制成骨细胞功能的中枢和外周机制。这一具体应用的重点是成骨细胞中 AR 表达的调节及其在糖皮质激素诱导的骨质流失情况下的病理生理学相关性。糖皮质激素通过一种尚不明确且仍有争议的作用机制引起骨质流失。我们的初步结果表明，1) 地塞米松诱导成骨细胞中的 αAR 表达，2) Adrα2 启动子含有 GRE 结合位点，3) 异丙肾上腺素（一种 bAR 激动剂）会加剧 WT 小鼠体内皮质酮诱导的骨质流失。鉴于这些结果，我们假设糖皮质激素的作用方式需要成骨细胞中的 AR 信号传导，特别是糖皮质激素增加成骨细胞中 AR 的表达和对 SNS 的反应性，从而放大 SNS 的抗成骨功能，导致导致骨质流失。为了检验这一假设，我们打算 1) 使用 AR-/- 小鼠来测试皮质酮对缺乏 AR 信号传导的小鼠的作用，2) 进行体外细胞信号传导和启动子分析，以表征下游糖皮质激素治疗的效果AR 和 Adr?2 转录，以及 3) 体内测试 b 阻滞剂对糖皮质激素引起的骨质流失的假定保护作用。简单总结：用于治疗哮喘或关节炎的糖皮质激素通过一种鲜为人知的机制引起骨质流失。我们将检验糖皮质激素通过增加骨对抑制骨形成的神经元信号的反应性对骨发挥这种作用的假设。这种机制的鉴定如果得到证实，将激励使用β受体阻滞剂作为预防性治疗，旨在阻止糖皮质激素引起的骨质流失。