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

描述(申请人提供)：骨重建，即成骨细胞和破骨细胞更新骨的过程，由激素、自分泌/旁分泌因子以及中枢和外周神经系统控制。事实上，我们已经证明，脂肪细胞衍生的激素瘦素通过下丘脑的继电器抑制骨形成，下丘脑神经元和骨骼之间的信号是通过交感神经系统(SNS)和成骨细胞中表达的β2肾上腺素能受体(β2AR)来传递的。在体内，阻断AR信号会增加骨形成，而刺激AR信号会减少骨形成。我们的长期目标是确定神经系统控制成骨细胞功能的中枢和外周机制。这一特定的应用集中在成骨细胞中？？AR表达的调节及其在糖皮质激素诱导的骨丢失中的病理生理学意义。糖皮质激素导致骨丢失的作用机制并不明确，但仍存在争议。我们的初步结果表明：1)地塞米松可诱导成骨细胞中？AR的表达，2)ADR？2启动子含有GRE结合部位，3)BAR激动剂异丙肾上腺素可加重WT小鼠体内皮质酮诱导的骨丢失。根据这些结果，我们推测糖皮质激素的作用方式需要成骨细胞中的AR信号，具体地说，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的抗骨生成功能，导致骨丢失。为了验证这一假设，我们打算1)使用AR-/-小鼠来测试皮质酮对缺乏AR信号的小鼠的影响，2)进行体外细胞信号和启动子分析来表征糖皮质激素对AR下游和ADR？2转录的影响，以及3)在体内测试b-受体阻滞剂对糖皮质激素诱导的骨丢失的可能保护作用。综述：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导致骨丢失。我们将测试糖皮质激素通过增加骨骼对抑制骨形成的神经元信号的反应性而在骨骼上发挥这种作用的假设。这种机制的确定，如果得到证实，将鼓励使用β-受体阻滞剂作为旨在阻止糖皮质激素诱导的骨丢失的预防性治疗。

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.