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.

为了确保老年退伍军人保持活跃和活动能力，并尽可能减少肌肉骨骼疼痛，新的 预防骨质疏松症和促进骨折后及时骨再生的方法有 必要的。这项合作研究汇集了一群具有不同背景的 VA 研究人员 观点、见解、模型和技术，协同解决导致 退伍军人中骨折的发病率和死亡率很高。各综合研究的总体策略 该项目是利用一种削弱骨骼或延迟骨骼修复的疾病的临床前模型来研究 增强甲状旁腺激素（PTH）促进骨形成能力的新方法，并评估 统一、严格地对待疾病和治疗对骨骼的影响。已经诊断不足和不足 如果骨质疏松症得到治疗，骨质疏松症可能会增加在退伍军人管理局医院接受治疗的脆性骨折的数量，而无需治疗。 用于早期检测的新工具和避免罕见但毁灭性副作用的新治疗策略 目前抑制骨质流失的疗法。解决这一未满足的临床需求，总体目标是确定 改善退伍军人骨骼健康并增强 PTH 骨合成代谢的治疗策略 发信号。此次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，增加骨吸收，抑制骨形成，或 阻碍骨折愈伤组织中软骨向骨的转变，从而改善临床管理 骨质疏松症的关键在于了解这些健康问题如何损害骨骼健康。该项目认识到 当患者年龄超过 50 岁时，高血压和骨质疏松症常常同时出现，并且 女性和男性退伍军人都容易患这两种慢性疾病。根据我们的初步研究 在标准的临床前高血压小鼠模型中，骨骼发生了这种情况，我们将通过以下方式研究其机制： 高血压会削弱骨骼，最终目标是确定一种新的治疗策略 预防骨质疏松症。具体来说，该项目的首要目标是检验性类固醇的假设， 即雌激素和睾酮，会影响骨量和骨质量的下降。 高血压发作。实现这一目标需要评估雌激素缺乏（或 睾酮缺乏）和高血压对小鼠骨抗骨折能力的影响。此外，通过 研究治疗和手术对骨骼和骨髓中基因和蛋白质表达的影响， 骨吸收和骨形成的标志物，以及骨细胞的数量和活性，该项目将 深入了解血压升高和交感神经张力升高如何对骨骼产生负面影响。在第二个 为了达到这个目的，我们将确定一种称为集落刺激因子 1 (CSF1) 的炎症因子是否是主要的炎症因子。 高血压中骨质流失的介质，并且就该细胞因子的细胞来源而言也是如此。这样做 需要在两种不同的小鼠品系中诱导高血压，这些小鼠品系被设计为阻止骨形成 （成熟成骨细胞）和骨感应细胞（骨细胞）产生 CSF1 或阻止血液内壁细胞 血管（内皮细胞）产生 CSF1。从机械研究过渡到转化研究， 我们将确定是否与间歇性甲状旁腺激素联合抑制 CSF1 信号传导 治疗，经批准的骨质疏松症治疗方法，和/或钙通道阻滞剂，经批准的治疗方法 对于高血压，可提高老年高血压小鼠的骨骼抵抗力。在所有这些目标中， 抗骨折能力的评估是全面的，不仅限于骨量和骨量，还包括 矩阵。通过了解高血压如何影响骨骼并通过合作研究团队的工作，新的 将寻求治疗策略来防止与年龄相关的骨折风险增加。这是需要的，因为 骨质疏松性骨折会导致退伍军人群体出现许多并发症，并且因为骨质疏松症 诊断不足和治疗不足。