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

基本信息

项目摘要

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 万起骨折,造成 190 亿美元的医疗费用 骨质疏松症是一种“无声疾病”,在骨折前往往没有明显症状, 很难诊断未来的骨折风险。 任何骨骼部位既往有骨折史,即使在控制骨矿物质密度后也是如此。 这种关系尚不清楚,但骨折很可能会引起全身性骨吸收反应,该反应在 某些情况会主动且永久地损害整个骨骼,但会导致全身性骨质流失。 骨折后的特征尚未得到彻底的表征,并且这种骨质流失的具体机制尚未确定 我们实验室的初步数据表明,骨折会主动减少骨小梁。 小鼠受伤后两周内远端骨骼部位的体积然而,存在显着的知识差距。 仍然需要关注影响骨折后骨丢失和恢复的因素,以及识别 识别这些因素的机制是迈向这种适应性反应的关键一步。 在拟议的研究中,我们将确定治疗目标和治疗机会窗口。 确定基于年龄和性别的差异、剂量依赖性(基于损伤严重程度)和具体 小鼠骨折后全身性骨丢失的机制,包括损伤引起的炎症和 我们认为:1)雄性和雌性小鼠会表现出不同的变化。 骨折后全身性骨质流失的严重程度,2)老年人从这种骨质流失中恢复的能力会减弱 小鼠,3)全身性骨质流失的程度将通过损伤的严重程度来预测,4)抑制 炎症细胞因子白细胞介素 6 (IL-6) 将减少全身骨质流失反应,5) 骨细胞- 缺陷小鼠将表现出骨吸收反应降低。在目标 1 中,我们将确定基于年龄和性别的情况。 在目标 2 中,我们将确定小鼠股骨骨折后全身骨质流失和恢复的差异。 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引起的骨丢失的贡献 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。 这些研究使用骨细胞功能障碍的遗传小鼠模型(Bcl-2 转基因小鼠)进行丧失反应。 将研究骨折主动全身性降低骨量的新假设,从而 这些研究将增加我们对所有骨骼部位未来骨折的风险。 急性损伤的全身影响,并可能导致旨在维持长期损伤的治疗策略 骨质疏松症患者的骨骼健康。

项目成果

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Blaine A. Christiansen其他文献

Blaine A. Christiansen的其他文献

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{{ truncateString('Blaine A. Christiansen', 18)}}的其他基金

Systemic Bone Loss Following Fracture in Humans
人类骨折后的全身性骨质流失
  • 批准号:
    10660721
  • 财政年份:
    2023
  • 资助金额:
    $ 35.42万
  • 项目类别:
Modification of Post-Traumatic Osteoarthritis Progression with Joint Unloading
通过关节卸载来改变创伤后骨关节炎的进展
  • 批准号:
    10549290
  • 财政年份:
    2020
  • 资助金额:
    $ 35.42万
  • 项目类别:
Acceleration of Alzheimer’s Disease Pathology Due to Osteoarthritis-Associated Inflammation
骨关节炎相关炎症加速阿尔茨海默病的病理变化
  • 批准号:
    10292125
  • 财政年份:
    2020
  • 资助金额:
    $ 35.42万
  • 项目类别:
Modification of Post-Traumatic Osteoarthritis Progression with Joint Unloading
通过关节卸载来改变创伤后骨关节炎的进展
  • 批准号:
    10320037
  • 财政年份:
    2020
  • 资助金额:
    $ 35.42万
  • 项目类别:
Modification of Post-Traumatic Osteoarthritis Progression with Joint Unloading
通过关节卸载来改变创伤后骨关节炎的进展
  • 批准号:
    9896699
  • 财政年份:
    2020
  • 资助金额:
    $ 35.42万
  • 项目类别:
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:
    10216174
  • 财政年份:
    2017
  • 资助金额:
    $ 35.42万
  • 项目类别:
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:
    9291294
  • 财政年份:
    2017
  • 资助金额:
    $ 35.42万
  • 项目类别:
The role of the inflammatory response in bone and cartilage changes following non
非手术后炎症反应在骨和软骨变化中的作用
  • 批准号:
    8918263
  • 财政年份:
    2012
  • 资助金额:
    $ 35.42万
  • 项目类别:
The role of the inflammatory response in bone and cartilage changes following non
非手术后炎症反应在骨和软骨变化中的作用
  • 批准号:
    8280849
  • 财政年份:
    2012
  • 资助金额:
    $ 35.42万
  • 项目类别:
The role of the inflammatory response in bone and cartilage changes following non
非手术后炎症反应在骨和软骨变化中的作用
  • 批准号:
    9116034
  • 财政年份:
    2012
  • 资助金额:
    $ 35.42万
  • 项目类别:

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