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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.

血清素是动物骨代谢的关键调节因子。小鼠模型显示，中枢（大脑）血清素通过抑制交感神经系统的有害作用，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。很明显， SSRIs直接抑制骨吸收，但长期使用SSRIs的中枢作用占主导地位通过增加交感神经系统（SNS）张力导致骨丢失，这抵消了早期效应并减少骨形成。与此相反，内源性5-羟色胺在调节人体免疫功能中的作用，骨骼健康没有得到很好的描述。然而，最近的研究表明，（SSRIs）增加骨折的风险但SSRIs在人类中发挥作用的机制尚未明确。最人类研究集中在评估骨密度，没有考虑重要的 SSRIs的时间依赖性效应，这导致了相互矛盾的数据。SSRIs对肌肉功能的影响，这也可能导致骨折的风险，才刚刚开始探索。我们已经开始取得进展在该领域，使用双X射线吸收测定法（DXA）、高分辨率外周血多模式方法定量计算机断层扫描（HRpQCT）、身体成分和身体功能测量。我们数据表明这是一种有用的方法。我们最近的研究表明，抗抑郁药的使用与减少身体表现以及皮质退化，后者可以用DXA和HR检测到- pQCT。特别是支持血清素的作用，参与者服用抗抑郁药， 5-羟色胺转运蛋白（如SSRIs和5-羟色胺去甲肾上腺素再摄取抑制剂）的亲和力使用其他类别抗抑郁药的患者中不存在的皮质缺陷。利用，DXA HRpQCT、经髂骨骨活检以及评估成骨细胞增殖、分化和增殖的新测定，基因表达，该提案的目标是确定组织，细胞和分子机制， SSRIs对人体肌肉骨骼系统的作用类似于在小鼠中证实的那些。模型这项建议的首要假设是，长期使用SSRIs和抗抑郁药，高/中等5-羟色胺转运体亲和力通过增加交感神经张力而降低骨形成，导致骨质流失和骨折。还将研究对肌肉质量和功能的影响。这项工作将有助于阐明血清素作为人体肌肉骨骼健康调节剂的作用，并指导在服用SSRIs和其他抗抑郁药的人群中进行肌肉骨骼筛查和治疗策略。由于长期使用SSRI是常见的，对骨骼健康的有害影响是重要的，减轻。此外，这样做可能会提供深入了解有针对性的人类肌肉骨骼调节。