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的一个众所周知的后果，但骨质流失从 30 多岁开始， 因此，与衰老相关的骨质流失有多种原因。 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。 该提议源于越来越多的临床前数据表明交感神经， 我们和其他人已经证明，它丰富地支配骨骼，控制骨骼重塑的过程。 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），导致骨吸收和Rankl依赖性增加 骨形成的时钟依赖性减少，从而导致骨丢失。然而，这些的临床相关性。 研究结果仍不清楚。 该提案的核心是三个关键观察结果：1）副交感神经和交感神经流出 与年龄成反比的变化，这些变化与骨质增生和骨质流失相关， 2) 阿尔茨海默病（AD）患者在发病早期就会过早发生骨质流失。 疾病发生在晚期 AD 典型的运动活动减少和骨骼卸载之前，这也是 与低副交感神经和高交感神经张力相关；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 骨骼对交感神经明显活动的反应，交感神经随着年龄的增长而变得功能失调。 根据这些观察结果，该提案的主要假设是副交感神经主导音调的转变 年轻人的交感神经张力在老年人中占主导地位，会导致与年龄相关的骨质流失。 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 密度累积，如果衰老过程中副交感神经张力过早或明显降低会导致骨质流失 （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 NE 的能力，并有助于与年龄相关的 骨质疏松症将采用遗传和药理学方法来改变关键成分。 自主神经系统的变化，突触前神经元与突触后骨细胞，以及年轻人与 这项工作将首次将先前与自主神经系统相关的发现与衰老小鼠结合起​​来。 它可以通过支持骨质疏松症的治疗来影响骨质疏松症的治疗。 使用的方法不仅可以抵消性激素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、渐进和持续影响。