Contribution of Phosphate to Inflammatory Bone Loss

磷酸盐对炎性骨质流失的影响

• 批准号: 10588936
• 负责人: GEORGE R. BECK
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-10-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10588936
• 关键词: 16S ribosomal RNA sequencing; Address; Adult; Age; Aging; Agreement; American; Antibiotics; Area; Bone Diseases; Bone Marrow; CD4 Positive T Lymphocytes; Cardiovascular Diseases; Cell Count; Cells; Cessation of life; Chronic; Clinical; Community Surveys; Consumption; Cultured Cells; Data; Dementia; Diet; Diet Habits; Dietary Intervention; Dietary Phosphorus; Digestion; Disease; Disease Progression; Elderly; Elements; Endocrine; Enteral; Etiology; Financial Hardship; Fracture; Germ-Free; Goals; Gonadal Steroid Hormones; Growth; Gut Mucosa; Health; High-Throughput Nucleotide Sequencing; Hip Fractures; Homeostasis; Hormones; Hospitalization; Immune response; Immune system; Individual; Inflammation; Inflammatory; Inflammatory Response; Inherited; Injections; Intake; Intervention; Intestinal permeability; Intestines; Kidney; Kidney Diseases; Knock-out; Knowledge; Leaky Gut; Longevity; Malignant Neoplasms; Measures; Medicare; Metabolism; Methodology; Methods; Minerals; Modeling; Mus; Mutation; Normal Range; Nutrient; Nutritional; Operative Surgical Procedures; Osteoporosis; Parathyroid gland; Pathology; Patients; Permeability; Phenotype; Phosphorus; Physiological; Predisposition; Premature aging syndrome; Prevention; Prevention strategy; Probiotics; Process; Proteins; Publishing; Quality of life; Rehabilitation therapy; Renal function; Reporting; Research; Retrospective Studies; Series; Serum; Signal Transduction; Small Intestines; Syndrome; T-Lymphocyte; TNF gene; Taxonomy; Testing; Therapeutic; Therapeutic Intervention; Tight Junctions; Tissues; Veterans; Veterans Health Administration; Woman; absorption; beneficiary; bone; bone healing; bone health; bone loss; bone mass; bone metabolism; bone quality; cell growth; clinically relevant; dietary; disability; dysbiosis; efficacy testing; fibroblast growth factor 23; fracture risk; gut inflammation; gut microbes; gut microbiome; gut microbiota; hospital readmission; improved; inflammatory bone loss; innovation; inorganic phosphate; male; microbiome; microbiome composition; military veteran; mouse model; neutralizing antibody; novel; novel strategies; receptor; reconstitution; response; secondary analysis

Project Summary/Abstract Objectives: The median age of veterans in 2018 was 65 and women make up the fastest growing share of veterans, estimated at 17% by 2040 (American Community Survey). Almost 25% are over 75 years old and 68% are 55 and older. Aging is associated with an increased vulnerability to a number of diseases including osteoporosis with the associated increased risk of fracture. Fractures have serious health consequences including lengthy rehabilitation and the most serious, hip fractures, may cause prolonged or permanent disability and almost always require hospitalization and major surgery. A recent retrospective, secondary analysis of National Veterans Health Administration Medicare beneficiaries concluded that one in three elderly male veterans who sustain a hip fracture die within one year. Another retrospective study of 41,331 veterans determined that approximately 18.3% of hip fracture patients were readmitted within 30 days and of those 48.5% died within one year. Therefore, prevention of fractures would represent a significant health intervention, improving longevity as well as quality of life in the veteran population. Nutritional intervention as a means to modulate health and disease represents a promising area of opportunity to improve health although sufficient data does not currently exist to optimally take advantage of this strategy. Research Plan: We have identified inorganic phosphate that is consumed in great excess by Americans as a nutritional element that strongly influences inflammation and bone quality and might be manipulated for improvement of bone mass and quality. Therefore, the goals of this study are to further investigate the value of controlling phosphate intake for the improvement of bone quality and reduction of inflammation. Our published and preliminary data strongly support the working model and hypothesis that high dietary Pi intake results in changes in the microbiome, compromised intestinal integrity, and chronic inflammation leading to bone loss, while a reduced Pi diet is beneficial to bone volume and reduces inflammation. Growing evidence strongly suggests that the gut microbiota can have profound systemic influence on health and disease although the details are only beginning to be uncovered. How, individual environmental elements such as nutrients alter the gut microbiota is even less understood. Pi is required for cell and bacterial growth and excess Pi is known to positively influence cell growth, and in some cases cause deregulated growth, leading to our general hypothesis that a sustained high Pi diet results in changes to the microbiome composition which results in inflammation and bone loss. Methods: Proposed studies will utilize a comprehensive series of innovative mouse models including Germ- Free, antibiotic treated, and T cell tracking mice to; 1) To determine if a sustained high phosphate diet generates increased intestinal inflammation, 2) To identify the mechanisms whereby the gut microbiome influences high dietary phosphate-induced bone loss including intestinal permeability and changes in microbiome content, and 3) To determine if the microbiome can be manipulated to modulate Pi homeostasis and bone metabolism. Clinical Relevance: Prevention of fractures will greatly reduce both the personal and financial burden to veterans relative to post-fracture treatment. These studies will be the first to investigate the effect of the common nutritional element particularly relevant to the dietary habits of Americans in Pi on gut inflammation and long-term changes to the gut microbiome. Results could unveil new clinically relevant prevention strategies to modulate mineral homeostasis that have broad consequences on health and disease.

项目总结/摘要 目标：2018年退伍军人的中位年龄为65岁，女性在其中所占比例增长最快。 退伍军人，估计到2040年将达到17%（美国社区调查）。近25%的人超过75岁， 68%为55岁及以上。老龄化与一系列疾病的易感性增加有关， 骨质疏松症与骨折风险增加相关。骨折会对健康造成严重后果 包括漫长的康复和最严重的髋部骨折，可能会导致长期或永久性的 残疾，几乎总是需要住院治疗和大手术。最近的一次回顾， 对国家退伍军人健康管理局医疗保险受益人的分析得出结论， 髋部骨折的男性退伍军人在一年内死亡。另一项对41，331名退伍军人的回顾性研究 确定大约18.3%的髋部骨折患者在30天内再次入院， 48.5%在一年内死亡。因此，预防骨折将是一项重要的健康干预措施， 提高退伍军人的寿命和生活质量。营养干预作为一种手段， 调节健康和疾病是改善健康的一个有希望的领域， 目前还没有数据来最佳地利用这一战略。 研究计划：我们已经确定了无机磷酸盐，这是消费在很大程度上超过了美国人作为一个 强烈影响炎症和骨质的营养元素，可能会被操纵， 改善骨量和骨质量。因此，本研究的目的是进一步探讨 控制磷酸盐的摄入量，以改善骨质量和减少炎症。我们的出版 初步数据强烈支持工作模型和假设，即高膳食Pi摄入导致 微生物组的变化、受损的肠道完整性和导致骨质流失的慢性炎症， 而减少Pi的饮食有益于骨体积并减少炎症。越来越多的证据表明 表明肠道微生物群可以对健康和疾病产生深远的系统性影响， 细节才刚刚开始被发现。如何，个别环境因素，如营养素改变 对肠道微生物群的了解更少。Pi是细胞和细菌生长所必需的，已知过量的Pi 积极影响细胞生长，并在某些情况下导致生长失调，导致我们的一般 假设持续的高Pi饮食导致微生物组组成的变化， 炎症和骨质流失。 方法：拟议的研究将利用一系列全面的创新小鼠模型，包括Germ- 自由，抗生素治疗，和T细胞跟踪小鼠; 1）以确定是否持续高磷酸盐饮食 产生增加的肠道炎症，2）为了确定肠道微生物组 影响高膳食磷酸盐诱导的骨丢失，包括肠渗透性和 微生物组含量，以及3）确定是否可以操纵微生物组以调节Pi稳态 和骨代谢。 临床相关性：预防骨折将大大减轻个人和经济负担， 相对于骨折后治疗的退伍军人。这些研究将是第一个调查的影响， 常见的营养元素尤其与美国人的饮食习惯有关，在Pi对肠道炎症的影响 以及肠道微生物组的长期变化。结果可以揭示新的临床相关的预防策略 调节对健康和疾病有广泛影响的矿物质体内平衡。

项目成果

Modulating phosphate consumption, a novel therapeutic approach for the control of cancer cell proliferation and tumorigenesis.

• DOI: 10.1016/j.bcp.2020.114305
• 发表时间: 2021-01
• 期刊: BIOCHEMICAL PHARMACOLOGY
• 影响因子: 5.8
• 作者: Arnst, Jamie L.;Beck, George R., Jr.
• 通讯作者: Beck, George R., Jr.

Sclerostin small-molecule inhibitors promote osteogenesis by activating canonical Wnt and BMP pathways.

• DOI: 10.7554/elife.63402
• 发表时间: 2023-08-10
• 期刊: eLife
• 影响因子: 7.7
• 作者: Sangadala S;Kim CH;Fernandes LM;Makkar P;Beck GR;Boden SD;Drissi H;Presciutti SM
• 通讯作者: Presciutti SM