Mechanisms of Systemic Bone Loss Following Femur Fracture in Mice

小鼠股骨骨折后全身性骨丢失的机制

• 批准号: 9980294
• 负责人: Blaine A. Christiansen
• 金额: $ 35.42万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9980294
• 关键词: Accounting; Acute; Affect; Age; Automobile Driving; BCL2 gene; Bilateral; Bone Density; Bone Matrix; Bone Resorption; Calcium; Cells; Cessation of life; Clinical Treatment; Data; Dependence; Diagnosis; Disease; Distant; Dose; Etiology; Exhibits; Female; Femoral Fractures; Fracture; Functional disorder; Future; Genetic; Goals; Health; Hibernation; Hormones; Human; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-6; Knowledge; Lactation; Lead; Mechanics; Mediator of activation protein; Medical Care Costs; Modeling; Movement; Mus; Osteocytes; Osteogenesis; Osteoporosis; Osteoporotic; Patients; Pharmacology; Porosity; Process; Recording of previous events; Recovery; Research; Risk; Risk Factors; Role; Severities; Site; Skeleton; Symptoms; Therapeutic; Time; Transgenic Mice; Translating; United States; base; bone; bone loss; bone mass; bone preservation; bone strength; bone turnover; cost; cytokine; fracture risk; insight; male; mouse model; musculoskeletal injury; novel; osteoporosis with pathological fracture; preservation; response; sex; skeletal; substantia spongiosa; systemic inflammatory response; therapeutic target

Project Summary/Abstract: Two million broken bones accounting for $19 billion dollars in medical costs occur each year because of the “silent disease” of osteoporosis, which often progresses with no noticeable symptoms prior to fracture, and is difficult to diagnose with respect to future fracture risk. Interestingly, the best predictor of future fracture risk is a previous history of fracture at any skeletal site, even after controlling for bone mineral density. The etiology of this relationship is unknown, but it is likely that fracture causes a systemic bone resorption response that under certain conditions can actively and permanently compromise the entire skeleton. However, systemic bone loss following fracture has not been thoroughly characterized, and the specific mechanisms of this bone loss have not been identified. Preliminary data from our lab show that bone fracture actively decreases trabecular bone volume at distant skeletal sites within two weeks post-injury in mice. However, significant knowledge gaps remain concerning factors that affect the loss and recovery of bone following fracture, and identification of mechanisms contributing to this adaptive response. Identification of these factors is a crucial step toward identifying therapeutic targets and the window of opportunity for treatment. In the proposed studies we will determine age- and sex-based differences, dose-dependence (based on injury severity), and specific mechanisms of systemic bone loss following fracture in mice, including injury-induced inflammation and osteocytic perilacunar remodeling. We hypothesize that: 1) male and female mice will exhibit different magnitudes of systemic bone loss following fracture, 2) recovery from this bone loss will be diminished in older mice, 3) the magnitude of systemic bone loss will be predicted by the severity of injury, 4) inhibition of the inflammatory cytokine interleukin 6 (IL-6) will reduce the systemic bone loss response, and 5) osteocyte- deficient mice will exhibit a reduced bone resorption response. In Aim 1 we will determine age- and sex-based differences in systemic bone loss and recovery following femur fracture in mice. In Aim 2 we will determine the dose-dependence of systemic bone loss based on injury severity, and the contribution of injury-induced inflammation, in particular IL-6. In Aim 3 we will determine the contribution of osteocytes to the systemic bone loss response using a genetic mouse model of osteocyte dysfunction (Bcl-2 transgenic mice). These studies will investigate the novel hypothesis that bone fracture actively decreases bone mass systemically, thereby increasing the risk of future fractures at all skeletal sites. These studies will expand our understanding of the systemic effects of an acute injury, and may lead to therapeutic strategies aimed at preserving the long-term skeletal health of osteoporotic patients.

项目摘要/摘要： 每年发生200万例骨折，相当于190亿美元的医疗费用，原因是 骨质疏松症的“静止性疾病”，通常在骨折前没有明显症状地进展，并且是 关于未来的骨折风险，很难诊断。有趣的是，对未来骨折风险的最好预测是 任何骨骼部位的既往骨折史，即使在控制了骨矿密度之后也是如此。该病的病因学 这种关系尚不清楚，但骨折很可能会引起全身骨吸收反应，在 某些情况可能会对整个骨骼造成积极和永久性的损害。然而，全身性骨丢失 继发性骨折的特征尚未完全确定，这种骨丢失的具体机制有 没有被确认身份。我们实验室的初步数据显示，骨折会使骨小梁明显减少 小鼠损伤后两周内远端骨骼部位的体积。然而，重大的知识差距 仍然关注影响骨折后骨丢失和恢复的因素，并确定 促进这种适应性反应的机制。确定这些因素是实现以下目标的关键一步 确定治疗目标和治疗的机会之窗。在建议的研究中，我们会 确定基于年龄和性别的差异、剂量依赖关系(基于损伤严重程度)和特定的 小鼠骨折后全身性骨丢失的机制，包括创伤诱导的炎症和 骨细胞性楔周重塑。我们假设：1)雄性和雌性小鼠将表现出不同的 骨折后全身骨丢失的程度，2)老年人从这种骨丢失中恢复的能力将会减弱 小鼠，3)全身骨丢失的程度将由损伤的严重程度预测，4)抑制 炎性细胞因子白介素6(IL-6)将减少全身骨丢失反应，5)骨细胞- 缺陷小鼠将表现出降低的骨吸收反应。在目标1中，我们将根据年龄和性别确定 小鼠股骨骨折后全身骨丢失和恢复的差异。在目标2中，我们将确定 基于损伤严重程度的全身性骨丢失的剂量依赖性，以及损伤诱导的贡献 炎症，特别是IL-6。在目标3中，我们将确定骨细胞对全身骨的贡献。 使用骨细胞功能障碍的遗传性小鼠模型(Bcl-2转基因小鼠)的丢失反应。这些研究 我将研究新的假说，即骨折积极系统地减少骨量，从而 增加了所有骨骼部位未来骨折的风险。这些研究将扩大我们对 急性损伤的全身性影响，并可能导致旨在保护长期 骨质疏松症患者的骨骼健康。