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

描述（由申请人提供）：骨重塑，即成骨细胞和破骨细胞更新骨的过程，受激素、自分泌/旁分泌因子以及中枢和外周神经系统控制。事实上，我们已经表明，脂肪细胞衍生的激素瘦素抑制骨形成通过下丘脑中继，下丘脑神经元和骨之间的信号是通过交感神经系统（SNS）和β 2-肾上腺素能受体（？2AR）在成骨细胞中表达。在体内，阻断？？AR信号增加骨形成，同时刺激？我们的长期目标是描述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监管？？成骨细胞中AR的表达及其在糖皮质激素诱导的骨丢失背景下的病理生理学相关性糖皮质激素诱导骨丢失的作用机制尚不清楚，且仍有争议。我们的初步结果表明：1）地塞米松诱导？？成骨细胞中AR的表达，2）Adr？2启动子含有GRE结合位点和3）异丙肾上腺素，一种bAR激动剂，在体内加重WT小鼠中皮质酮诱导的骨丢失。根据这些结果，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，特别是糖皮质激素增加？？成骨细胞中的AR表达和对SNS的反应性，从而放大SNS的抗成骨功能，导致骨丢失。为了验证这一假设，我们打算1）使用？？AR-/-小鼠，以测试皮质酮在缺乏？AR信号传导，2）进行体外细胞信号传导和启动子分析，以表征糖皮质激素治疗对AR下游的影响？在Adr？2转录，和3）在体内测试B-阻断剂对糖皮质激素诱导的骨丢失的推定保护作用。简要总结：糖皮质激素用于治疗哮喘或关节炎会通过一种尚不清楚的机制诱导骨丢失。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来对骨发挥这种作用的假设。这种机制的确定，如果得到证实，将是一个激励使用β受体阻滞剂作为预防性治疗，旨在阻止糖皮质激素诱导的骨丢失。

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.