Senile Osteoporosis as a Neuroskeletal Disease

项目摘要 骨质疏松症是性激素缺乏的一个众所周知的后果，但骨质流失开始于30年代， 在性腺衰竭后持续稳定。因此，与衰老相关的骨质流失有几个原因。 在这个应用程序中，我们问骨质疏松症是否可能有神经骨骼成分。 该提议源于越来越多的临床前数据，这些数据表明交感神经， 它丰富地支配着骨骼，控制着骨骼重塑的过程。我们和其他人已经证明， 小鼠中交感神经的激活引起去甲肾上腺素（NE）的释放和交感神经的刺激。 成骨细胞中的β2肾上腺素能受体（β2AR），导致骨吸收的Rankl依赖性增加， 导致骨形成的时钟依赖性减少，从而导致骨丢失。然而，这些临床相关性 调查结果仍不清楚。 三个关键的观察是这个建议的核心：1）副交感神经和交感神经流出 随着年龄以相反的方式变化并且这些变化与骨增加和骨丢失相关， 2）阿尔茨海默病（AD）患者的骨丢失过早发生，在早期阶段， 在晚期AD典型的自发活动减少和骨骼卸载之前， 与低副交感神经和高交感神经张力有关; 3）我们的数据支持存在一个 内源性稳态系统，由骨细胞中的去甲肾上腺素转运蛋白（NET）驱动，控制骨细胞中的 骨骼对交感神经明显活动的反应，交感神经随着年龄的增长而功能失调。基于 这些观察，这个建议的主要假设是，从一个占主导地位的副交感神经紧张的转变， 在年轻个体中，交感神经张力占主导地位，在老年个体中，交感神经张力占主导地位，这有助于与年龄相关的骨丢失。 我们设计了实验来确定高中枢副交感神经张力是否对骨骼有益 密度增加，以及如果在老化过程中副交感神经张力过早或明显减少导致骨质流失 (Aim 1）。在目标2中，我们将确定随着年龄的增长，骨细胞中NE摄取活性的降低是否会降低骨细胞中NE的表达。 骨骼处理交感神经释放的NE的能力，并有助于与年龄相关的 骨质疏松遗传和药理学方法将用于这两个目标，以改变关键成分 在自主神经系统中，突触前神经元与突触后骨细胞，年轻人与 衰老的老鼠这项工作将首次把以前的研究结果与自主神经系统， 骨到临床相关的背景下老化。它可能会影响骨质疏松症的管理， 使用的方法不仅抵消了性激素缺乏对骨骼的负面影响， 自主神经系统对骨稳态的早期、渐进和持续影响。

Project Abstract Osteoporosis is a well known consequence of sex-hormone deficiency, but bone loss starts in the 30s and continues steadily after gonadal failure. There are thus several causes for the bone loss associated with aging. In this application, we ask whether osteoporosis might have a neuroskeletal component. The proposal stems from an increasing amount of preclinical data suggesting that sympathetic nerves, which richly innervate the skeleton, control the process of bone remodeling. We and others have shown that activation of sympathetic nerves in mice causes the release of norepinephrine (NE) and the stimulation of the β2-adrenergic receptors (β2AR) in osteoblasts, leading to a Rankl-dependent increase in bone resorption and to a Clock-dependent reduction in bone formation, hence to bone loss. However, the clinical relevance of these findings remains unclear. Three critical observations are at the core of this proposal: 1) parasympathetic and sympathetic outflow changes in an inverse manner with age and these changes correlate with bone accrual and bone loss, respectively; 2) bone loss occurs prematurely in patients with Alzheimer disease (AD), at early stage of the disease, prior to reduced locomotor activity and skeletal unloading typical of late-stage AD, and this is also associated with low parasympathetic and high sympathetic tone; 3) our data support the existence of an endogenous homeostatic system, driven by the norepinephrine transporter (NET) in osteocytes, controlling the skeleton’s response to overt activity of sympathetic nerves, which become dysfunctional upon aging. Based on these observations, the main hypothesis of this proposal is that a shift from a dominant parasympathetic tone in young individuals to a dominant sympathetic tone in older individuals contributes to age-related bone loss. We have designed experiments to determine if a high central parasympathetic tone is beneficial for bone density accrual, and if a premature or overt reduction in parasympathetic tone during aging leads to bone loss (Aim 1). In Aim 2, we will determine if a reduction in NE uptake activity in osteocytes with age reduces the capacity of the skeleton to handle NE released from sympathetic nerves and contributes to age-related osteoporosis. Genetic and pharmacological approaches will be used in both aims to alter crucial components of the autonomic nervous system, in presynaptic neurons versus post-synaptic bone cells, and in young versus aging mice. This work will for the first time put previous findings related to the autonomic nervous system and bone into the clinically relevant context of aging. It could impact the management of osteoporosis by supporting the use of approaches that counteract not only the negative effect of sex hormone deficiency on bone but also the early, progressive and sustained effects of the autonomic nervous system on bone homeostasis.