Serotonin and Skeletal Health

血清素和骨骼健康

基本信息

批准号：
10674962
负责人：
MARCELLA Donovan WALKER
金额：
$ 72.2万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2027-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10674962
关键词：
Acute Adrenergic beta-Antagonists Adult Affect Affinity Aging American Animals Antidepressive Agents Area Basic Science Biological Assay Biopsy Body Composition Body measure procedure Bone Density Bone Resorption Brain Categories Chronic Clinical Research Communities Data Deterioration Drug usage Elderly Fluoxetine Fracture Gene Expression Goals Health Height Hip region structure Human Measurement Mediating Mental Depression Meta-Analysis Molecular Mus Muscle Muscle function Musculoskeletal Musculoskeletal Development Musculoskeletal System Norepinephrine Not Hispanic or Latino Observational Study Osteoblasts Osteogenesis Participant Peripheral Pharmaceutical Preparations Physical Function Physical Performance Physical activity Porosity Postmenopause Proliferating Psychotherapy Publishing Radial Resolution Resources Risk Roentgen Rays Role Safety Selective Serotonin Reuptake Inhibitor Serotonin Site Skeletal Development Structure Sympathetic Nervous System Time Tissues Trabecular Bone Score Traction Translating Vertebral column Washington Woman Work X-Ray Computed Tomography antidepressant effect bone bone health bone loss bone mass bone metabolism bone turnover cohort comorbidity falls fracture risk high risk human data human old age (65+)indexing inhibitor insight interdisciplinary approach mouse model multi-ethnic multimodality muscle form novel osteoblast differentiation osteoblast proliferation osteoporosis with pathological fracture population based post stroke prevent primary outcome reuptake screening serotonin transporter skeletal treatment strategy

项目摘要

Serotonin is a key regulator of bone metabolism in animals. Murine models show that central (brain) serotonin positively regulates bone mass by inhibiting the deleterious effects of the sympathetic nervous system on osteoblasts. In mice, selective serotonin reuptake inhibitors (SSRIs) have time-dependent effects. Acutely, SSRIs directly inhibit osteoclastic bone resorption, but with chronic use the central effect of SSRIs predominate causing bone loss by increasing sympathetic nervous system (SNS) tone, which counteracts the early effects on resorption and reduces bone formation. In contrast, the role of endogenous serotonin in regulating human skeletal health is not well delineated. Recent work, however, indicates that (SSRIs) increase the risk of fracture by two times, but the mechanisms by which SSRIs do so in humans have not been clearly defined. Most human studies have focused on assessing areal bone mineral density and have not considered the important time-dependent effects of SSRIs, which has led to conflicting data. The effects of SSRIs on muscle function, which may also contribute to fracture risk, have only started to be explored. We have begun to make progress in this area using a multimodal approach with dual x-ray absorptiometry (DXA), high-resolution peripheral quantitative computed tomography (HRpQCT), body composition and measurement of physical function. Our data indicate this is a useful approach. Our recent work shows antidepressant use is associated with reduced physical performance as well as cortical deterioration, the latter of which can be detected with DXA and HR- pQCT. Supporting a role for serotonin in particular, participants taking antidepressants with moderate or high affinity for the serotonin transporter (such as SSRIs and serotonin norepinephrine reuptake inhibitors) had cortical deficits that were not present in those using other categories of antidepressants. Utilizing, DXA HRpQCT, transiliac bone biopsy as well as novel assays assessing osteoblast proliferation, differentiation and gene expression, the goal of this proposal is to determine if the tissue, cellular and molecular mechanisms by which SSRIs act on the musculoskeletal system in humans is analogous to those demonstrated in murine models. The overarching hypothesis of this proposal is that chronic use of SSRIs and antidepressants with high/moderate serotonin transporter affinity decrease bone formation by increasing sympathetic tone, which leads to bone loss and fracture. Effects on muscle mass and function will also be investigated. This work will help elucidate the role of serotonin as a regulator of human musculoskeletal health and guide the development of musculoskeletal screening and treatment strategies in those taking SSRIs and other antidepressants. Because long-term SSRI use is common, detrimental effects on skeletal health are important to elucidate and mitigate. Moreover, doing so may provide insight into targetable human musculoskeletal regulators.

5-羟色胺是动物骨代谢的关键调节剂。鼠模型表明中央（脑）5-羟色胺通过抑制交感神经系统对骨量的积极调节成骨细胞。在小鼠中，选择性5-羟色胺再摄取抑制剂（SSRIS）具有时间依赖性作用。敏锐 SSRI直接抑制整骨骨吸收，但长期使用SSRIS的中心作用通过增加交感神经系统（SNS）音调导致骨质丧失，这抵消了早期影响吸收并减少骨形成。相反，内源5-羟色胺在调节人的作用骨骼健康没有很好地描述。但是，最近的工作表明（SSRI）增加了骨折的风险到两次，但是SSRI在人类中这样做的机制尚未得到明确定义。最多人类研究的重点是评估面积的骨矿物质密度，并未考虑重要的 SSRI的时间依赖性效果，导致数据冲突。 SSRI对肌肉功能的影响，这也可能导致骨折风险，仅开始探索。我们已经开始进步在此区域中，使用双模式方法采用双X射线吸收法（DXA），高分辨率外围定量计算机断层扫描（HRPQCT），身体功能的身体组成和测量。我们的数据表明这是一种有用的方法。我们最近的工作表明抗抑郁药与减少有关身体性能以及皮质恶化，后者可以用DXA和HR-检测 PQCT。特别是支持5-羟色胺的角色，参与者服用中等或高的抗抑郁药对5-羟色胺转运蛋白的亲和力（例如SSRIS和5-羟色胺去甲肾上腺素再摄取抑制剂）使用其他类别的抗抑郁药的那些不存在的皮质缺陷。利用DXA HRPQCT，跨性骨活检以及评估成骨细胞增殖，分化和基因表达，该提议的目的是确定组织，细胞和分子机制是否通过哪个SSRI对人类的肌肉骨骼系统作用类似于鼠型号。该提案的总体假设是长期使用SSRI和抗抑郁药高/中度的5-羟色胺转运蛋白转运蛋白的亲和力通过增加交感神经来减少骨形成，这导致骨质流失和断裂。还将研究对肌肉质量和功能的影响。这项工作将帮助阐明5-羟色胺作为人类肌肉骨骼健康的调节剂的作用，并指导发展服用SSRI和其他抗抑郁药的肌肉骨骼筛查和治疗策略。由于长期使用SSRI是常见的，因此对骨骼健康的有害影响对于阐明和缓解。此外，这样做可能可以洞悉目标人类肌肉骨骼调节剂。