Senile Osteoporosis as a Neuroskeletal Disease

老年骨质疏松症作为一种神经骨骼疾病

• 批准号: 9282248
• 负责人: Florent Elefteriou
• 金额: $ 39.63万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9282248
• 关键词: Acetylcholine; Address; Adult; Age; Age-Related Bone Loss; Age-Related Osteoporosis; Age-Years; Aging; Alzheimer' s Disease; Autonomic nervous system; Blood - brain barrier anatomy; Bone Density; Bone Marrow; Bone Resorption; Bone remodeling; Brain; Buffers; Clinical; Data; Developed Countries; Dimensions; Disease; Elderly; Environment; Failure; Fiber; Fracture; Genetic; Gonadal Steroid Hormones; Hip region structure; Homeostasis; Impairment; Incidence; Individual; Isoproterenol; Lead; Life; Longevity; Longitudinal Studies; Menopause; Motor Activity; Mus; Nerve; Nervous system structure; Neuraxis; Neurotransmitters; Norepinephrine; Organ; Osteoblasts; Osteocytes; Osteogenesis; Osteoporosis; Patients; Permeability; Pharmacology; Process; Rattus; Regulation; Role; Senile Osteoporosis; Signal Transduction; Site; Skeleton; Synapses; System; Time; Woman; Work; age related; autonomic nerve; base; beta-2 Adrenergic Receptors; bone; bone aging; bone cell; bone loss; bone mass; choline transporter; clinically relevant; design; esterase inhibitor; experience; experimental study; fracture risk; gain of function; hormone deficiency; loss of function; men; mouse model; noradrenaline transporter; older patient; pre-clinical; premature; presynaptic neurons; receptor; response; skeletal; skeletal unloading; stem; tool; uptake

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.

项目摘要 骨质疏松症是性激素缺乏症的众所周知的结果，但骨质流失始于30年代， 性腺衰竭后静静地继续。因此，有几种与衰老相关的骨质流失的原因。 在此应用中，我们询问骨质疏松症是否可能具有神经骨骼成分。 提案步骤从越来越多的临床前数据提出，这表明交感神经， 富裕地支配骨骼，控制骨骼重塑的过程。我们和其他人表明 小鼠交感神经的激活导致去甲肾上腺素（NE）的释放，并刺激 成骨细胞中的β2-肾上腺素能受体（β2AR），导致骨骼分辨率的RANKL依赖性增加和 骨骼形成的时钟依赖性减少，因此导致骨质流失。但是，这些相关性 发现尚不清楚。 该提案的核心是三个关键观察：1）副交感神经和交感神经出口 随着年龄的增长而变化的变化，这些变化与骨骼的骨骼和骨质流失相关， 2）骨质流失过早发生在阿尔茨海默氏病（AD）的患者中 疾病，在降低运动活性和典型的后期AD的骨骼卸载之前，这也是 与低副交感神经和高同情性语气有关； 3）我们的数据支持存在 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 骨骼对交感神经的公开活动的反应，衰老后会变得功能失调。基于 这些观察结果是，该提议的主要假设是从主要的副交感神经语调转变 在年轻人中，年轻人的同情性语调在老年人中有助于与年龄相关的骨质流失。 我们设计了实验来确定高中央副交感神经是否对骨骼有益 密度准确性，如果在衰老期间过早或明显降低副交感神经张力会导致骨质流失 （目标1）。在AIM 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 骨骼处理从交感神经释放的NE的能力并有助于与年龄有关 骨质疏松症。遗传和药物方法将用于改变关键组成部分 自主神经系统，突触前神经元与突触后骨细胞中的 衰老的小鼠。这项工作将首次提出与自主神经系统和 骨骼进入临床相关的衰老环境。它可能通过支持来影响骨质疏松症的管理 使用的方法不仅可以抵消性马酮缺乏对骨骼的负面影响，还可以 自主神经系统对骨稳态的早期，进行性和持续的影响。