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，但骨质流失始于30多岁和 在性腺功能衰竭后持续稳定。因此，与衰老相关的骨质流失有几个原因。 在这一应用中，我们询问骨质疏松症是否可能有神经骨骼成分。 这一建议源于越来越多的临床前数据表明交感神经， 它丰富地支配着骨骼，控制着骨骼重建的过程。我们和其他人已经证明了 激活小鼠的交感神经可引起去甲肾上腺素(NE)的释放和兴奋 成骨细胞中的β2肾上腺素能受体(β2AR)，导致骨吸收和骨吸收增加 与生物钟相关的骨形成减少，从而导致骨丢失。然而，这些指标的临床相关性 调查结果仍不清楚。 这一提议的核心是三个关键观察：1)副交感神经和交感神经流出 随着年龄的变化呈相反的方式变化，这些变化与骨积累和骨丢失相关， 2)阿尔茨海默病(AD)患者过早地发生骨丢失，在 疾病，在运动活动减少和骨骼卸载之前，这是晚期AD的典型特征，这也是 与低副交感和高交感音调有关；3)我们的数据支持 内源性动态平衡系统，由骨细胞中的去甲肾上腺素转运体(NET)驱动，控制 骨骼对交感神经显性活动的反应，交感神经随着年龄的增长而变得功能失调。基于 这些观察，这个建议的主要假设是，从占主导地位的副交感音调转变 在年轻人中，交感神经占优势的老年人会导致与年龄相关的骨丢失。 我们设计了实验，以确定高中枢副交感神经张力是否对骨骼有益 密度增加，以及如果在衰老过程中副交感神经张力过早或明显降低导致骨丢失 (目标1)。在目标2中，我们将确定骨细胞中NE摄取活性的降低是否会随着年龄的增长而降低 骨骼处理交感神经释放的去甲肾上腺素的能力，并与年龄相关 骨质疏松。这两个目标都将使用遗传和药理学方法来改变关键成分 自主神经系统，突触前神经元与突触后骨细胞，以及年轻与 老化的小鼠。这项工作将首次将之前关于自主神经系统和 与衰老相关的临床背景下的骨骼。它可能通过支持骨质疏松症的治疗而影响治疗 使用不仅抵消性激素缺乏对骨骼的负面影响的方法，而且还 自主神经系统对骨骼稳态的早期、渐进和持续的影响。

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.