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

为了确保年迈的退伍军人在尽可能少的肌肉骨骼疼痛的情况下保持活跃和活动，新的 预防骨质疏松症和促进骨折后及时骨再生的方法有 这是必要的。这项合作研究汇集了一组退伍军人管理局调查人员，他们具有不同的 观点、见解、模型和技术，协同解决导致以下问题的主要临床问题 退伍军人发病率高，死亡率高，是一种骨折。每一项整合的整体研究策略 该项目是使用一种疾病的临床前模型，这种疾病要么削弱骨骼，要么推迟骨骼修复，以调查 增强甲状旁腺激素(PTH)促进骨形成能力的新方法，并评估 疾病和治疗对骨骼的影响是统一、严格的。已经被低估和低估了- 治疗后，骨质疏松症可能会增加在退伍军人医院接受治疗的脆性骨折的数量 早期发现的新工具和避免罕见但破坏性副作用的新治疗策略 目前抑制骨质流失的治疗方法。针对这一未得到满足的临床需求，总体目标是确定 改善退伍军人骨健康和增强甲状旁腺激素骨合成代谢的治疗策略 发信号。这项合作将解决这个最重要的假设：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 阻碍骨折骨痂中软骨向骨的转变，从而改善临床治疗 骨质疏松的关键在于了解这些健康问题是如何损害骨骼健康的。这个项目认识到 高血压和骨质疏松症通常随着患者50岁以上的年龄增长而同时发展， 女性和男性退伍军人都容易患上这两种慢性病。基于我们对什么的初步研究 在标准的临床前高血压小鼠模型中，骨发生了变化，我们将通过 哪种高血压会削弱骨骼，最终目标是确定一种新的治疗策略 预防骨质疏松症。具体地说，该项目的第一个目标将是验证性类固醇， 即雌激素和睾酮，会影响骨量和骨质量的下降，这种下降是由 高血压的发病。实现这一目标需要评估雌激素缺乏(或 睾丸激素缺乏)和高血压对小鼠骨骼抗折性的影响。此外，通过 研究治疗和手术对骨和骨髓中基因和蛋白表达的影响 骨吸收和骨形成的标记物，以及骨细胞的数量和活性，该项目将 洞察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 目的：我们将确定一种称为集落刺激因子1(CSF1)的炎性因子是否是一种主要的 高血压时骨丢失的中介物，并与该细胞因子的细胞来源有关。这样做的话 需要在两个不同的小鼠品系中诱导高血压，这些品系被设计成防止骨形成 (成熟成骨细胞)和骨感应细胞(骨细胞)产生CSF1或阻止细胞进入血液 血管(内皮细胞)产生CSF1。从机械学研究过渡到翻译研究， 我们将确定是否联合间歇性甲状旁腺激素抑制CSF1信号转导 治疗，一种被批准的骨质疏松症治疗方法，和/或钙通道阻滞剂，一种被批准的治疗方法 对于高血压，改善老年高血压小鼠骨骼的抗折性。在所有这些目标中， 骨折抗力的评估是全面的，超越了骨量和骨体积，包括 矩阵。通过了解高血压是如何影响骨骼的，通过合作研究团队，新的 将寻求治疗策略，以防止与年龄相关的骨折风险增加。这是必要的，因为 骨质疏松性骨折在退伍军人中会导致许多并发症，因为骨质疏松症 诊断不足，治疗不足。

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.