BCCMA: Foundational Research to Act Upon and Resist Conditions Unfavorable to Bone (FRACTURE CURB): Role of Hypertension in Favoring Osteoporosis

BCCMA：针对和抵抗不利于骨骼的条件（骨折遏制）的基础研究：高血压在促进骨质疏松症中的作用

• 批准号: 10483572
• 负责人: Jeffry Stephen Nyman
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10483572
• 关键词: Address; Adult; Affect; Age; Age Years; Aging; Amlodipine; Anabolism; Angiotensin II; Animals; Blood; Blood Pressure; Blood Vessels; Bone Marrow; Bone Regeneration; Bone Resorption; Bone callus; Calcium Channel Blockers; Cartilage; Catecholamines; Cell Count; Cell Line; Cells; Chronic; Chronic Disease; Clinical; Clinical Management; Clinical Research; Collaborations; Combined Modality Therapy; Cytoprotection; DOCA; Diabetes Mellitus; Diagnosis; Disease; Disease model; Dual-Energy X-Ray Absorptiometry; Early Diagnosis; Endothelial Cells; Engineering; Ensure; Estrogen deficiency; Estrogens; Euthanasia; Female; Fracture; Gene Expression; Gene Proteins; Goals; Gonadal Steroid Hormones; Health; Health Personnel; Hip Fractures; Hospitals; Hypertension; Implant; Inflammatory; Injections; Knock-out; Lead; Link; Longevity; LoxP-flanked allele; Macrophage Colony-Stimulating Factor; Macrophage Colony-Stimulating Factor Receptor; Marrow; Mechanics; Mediator; Medical; Metabolism; Modeling; Monitor; Morbidity - disease rate; Mouse Strains; Mus; Musculoskeletal Pain; Operative Surgical Procedures; Orchiectomy; Osteoblasts; Osteocytes; Osteogenesis; Osteoporosis; Osteoporosis prevention; Outcome; Outcome Measure; Ovariectomy; PTH gene; Pathway interactions; Patients; Population; Positioning Attribute; Pre-Clinical Model; Predisposition; Prevalence; Prevention; Prevention approach; Production; Research; Research Personnel; Resistance; Risk; Role; Services; Signal Pathway; Signal Transduction; Sodium Chloride; Source; Tail; Tamoxifen; Techniques; Testing; Testosterone; Therapeutic; Time; Tissues; United States Department of Veterans Affairs; Urine; Veterans; age related; aged; blood pressure reduction; bone; bone cell; bone fracture repair; bone health; bone loss; bone mass; bone quality; bone repair; bone strength; cadherin 5; cytokine; dentin matrix protein 1; experimental study; fracture risk; fragility fracture; hormonal signals; hypertensive; improved; in vitro Model; in vivo; inducible Cre; inhibitor; innovation; insight; loss of function; male; military veteran; mortality; mouse Cre recombinase; mouse model; negative affect; normotensive; novel; novel strategies; novel therapeutic intervention; osteoclastogenesis; osteoporosis with pathological fracture; pre-clinical; prevent; protein expression; research study; sex; side effect; tool; translatable strategy; translational study; treatment effect; treatment group; treatment strategy; urinary

To ensure aging Veterans remain active and mobile with as little musculoskeletal pain as possible, new approaches to the prevention of osteoporosis and promotion of timely bone regeneration following a fracture are necessary. This collaborative research study brings together a group of VA investigators with diverse perspectives, insights, models, and techniques, to synergistically attack a major clinical problem that leads to high morbidity and mortality among Veterans, a bone fracture. The overall research strategy of each integrated project is to use pre-clinical models of a disease that either weakens bone or delays bone repair, to investigate novel ways to enhance the ability of parathyroid hormone (PTH) to promote bone formation, and to assess disease and treatment effects on bone in a unified, stringent manner. Already under-diagnosed and under- treated, osteoporosis is likely to increase the number of fragility fractures being treated at VA hospitals without novel tools for early detection and novel treatment strategies that circumvent the rare but devastating side effects of current therapies that inhibit bone loss. Addressing this unmet clinical need, the overall aims are to identify therapeutic strategies to improve bone health among Veterans and to enhance the bone anabolism of PTH signaling. The collaboration will address this overarching hypothesis: health problems disproportionately affecting Veterans activate signaling pathways that increase bone resorption, suppress bone formation, or impede the transition of cartilage to bone in a fracture callus such that improvements in the clinical management of osteoporosis lie in understanding how these health problems hurt bone health. This project recognizes that hypertension and osteoporosis often develop together as patients grow older beyond 50 years of age and that female and male Veterans are susceptible to both chronic diseases. Based on our preliminary studies of what happens to bone in standard pre-clinical mouse models of hypertension, we will investigate a mechanism by which hypertension weakens bone with the ultimate goal of identifying a new therapeutic strategy in the prevention of osteoporosis. Specifically, the first aim of the project will be to test the hypothesis that sex steroids, namely estrogen and testosterone, influence the decline in bone mass and bone quality that occurs with the onset of hypertension. Achieving this goal involves assessing the relative effect of estrogen deficiency (or testosterone deficiency) and hypertension on the fracture resistance of mouse bone. Furthermore, by investigating treatment and surgery effects on gene and protein expression in bone and bone marrow, on markers of bone resorption and bone formation, and on the number and activity of bone cells, the project will provide insight into how rising blood pressure and rising sympathetic tone negatively affects bone. In the second aim, we will ascertain whether an inflammatory factor known as colony stimulating factor 1 (CSF1) is a major mediator of bone loss in hypertension and do so with respect to the cellular source of this cytokine. Doing so requires the induction of hypertension in 2 different mouse strains engineered to either prevent bone forming (mature osteoblasts) and bone sensing cells (osteocytes) from producing CSF1 or preventing cells lining blood vessels (endothelial cells) from producing CSF1. Transitioning from mechanic studies to translational studies, we will determine whether inhibiting CSF1 signaling in combination with intermittent parathyroid hormone treatment, an approved therapy for osteoporosis, and/or with a calcium channel blocker, an approved therapy for hypertension, improves the fracture resistance of bone in aged, hypertensive mice. In all these aims, the assessment of fracture resistance is comprehensive going beyond bone mass and bone volume to include the matrix. By understanding how hypertension affects bone and by working as a collaborative research team, new therapeutic strategies will be sought to prevent the age-related increase in fracture risk. This is needed because osteoporotic fractures lead to many complications in Veteran population and because osteoporosis is underdiagnosed and undertreated.

为了确保老化的退伍军人保持活跃和流动性，并尽可能少肌肉骨骼疼痛 骨折后预防骨质疏松症和促进及时骨再生的方法是 必要的。这项合作研究汇集了一群VA调查人员， 观点，见解，模型和技术，以协同攻击主要的临床问题，导致 退伍军人的高发病和死亡率高，骨折。每个集成的总体研究策略 项目是使用疾病的临床前模型，该模型可以削弱骨骼或延迟骨修复，以调查 增强甲状旁腺激素（PTH）促进骨骼形成并评估的新方法 疾病和治疗以统一，严格的方式对骨骼的影响。已经诊断不足和 经过治疗，骨质疏松症可能会增加在没有VA医院治疗的脆性骨折的数量 新颖的工具，用于早期检测和新型治疗策略，这些工具规避了罕见但毁灭性的副作用 当前抑制骨质流失的疗法。解决这种未满足的临床需求，总体目的是确定 改善退伍军人骨骼健康并增强PTH的骨骼合成代谢的治疗策略 信号。合作将解决这一总体假设：健康问题不成比例 影响退伍军人激活信号通路，以增加骨吸收，抑制骨形成或 阻碍软骨向骨骼过渡到骨折的愈伤组织中，以改善临床管理 骨质疏松症在于了解这些健康问题如何损害骨骼健康。这个项目认识到 高血压和骨质疏松症经常随着患者的年龄增长，通常会一起发展，并且 男性和男性退伍军人都容易受到两种慢性疾病的影响。根据我们对什么的初步研究 在标准的临床前小鼠高血压模型中发生骨骼，我们将通过 高血压以确定新的治疗策略的最终目标削弱了骨骼 预防骨质疏松症。具体而言，该项目的第一个目的是检验性类固醇， 即雌激素和睾丸激素，影响骨质量和骨质的下降 高血压发作。实现此目标涉及评估雌激素缺乏症的相对效应（或 睾丸激素缺乏症）和小鼠骨骼抗骨折性的高血压。此外，由 研究治疗和手术对骨和骨髓中基因和蛋白质表达的影响， 骨吸收和骨形成的标记，以及骨细胞的数量和活性，该项目将 提供有关血压升高和交感神经语调如何对骨骼产生负面影响的洞察力。在第二个 目的，我们将确定称为菌落刺激因子1（CSF1）的炎症因子是主要的 高血压中骨质流失的介体，并相对于该细胞因子的细胞来源。这样做 需要在设计的2种不同的小鼠菌株中诱导高血压，以防止骨骼形成 （成熟的成骨细胞）和骨传感细胞（骨细胞）产生CSF1或防止细胞衬里血液 产生CSF1的血管（内皮细胞）。从机械研究过渡到翻译研究， 我们将确定是否抑制CSF1信号与间歇性甲状旁腺激素结合 治疗，经过批准的骨质疏松症和/或与钙通道阻滞剂（批准的疗法） 为了进行高血压，可以改善老年高血压小鼠骨骼的抗骨折性。在所有这些目标中， 骨折抗性的评估是全面的，超出了骨骼质量和骨骼体积，包括 矩阵。通过了解高血压如何影响骨骼并通过合作研究团队工作，新的 将寻求治疗策略，以防止与年龄相关的骨折风险增加。这是需要的 骨质疏松性骨折导致退伍军人人口的许多并发症，因为骨质疏松症是 未经诊断和治疗未经诊断。