Role Of Bone Blood Flow In Bone Loss Following SCI

骨血流量在 SCI 后骨质流失中的作用

• 批准号: 9236938
• 负责人: Joshua F. Yarrow
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-10-01 至 2018-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9236938
• 关键词: Address; Animal Model; Animals; Bicycling; Blood; Blood Vessels; Blood flow; Bone Density; Clinical Trials; Conscious; Contusions; Data; Development; Distal; Endothelium; Exercise; Femur; Fluorochrome; Food; Food Additives; Fracture; Glucocorticoids; Hemorrhage; Herb; Human; Injury; Ischemia; Life; Limb structure; Locomotor Recovery; Measures; Mechanical Stimulation; Mechanics; Microspheres; Minerals; Modeling; Morphology; Motor; Mus; Musculoskeletal; Osteoblasts; Osteoclasts; Osteogenesis; Osteoporosis; Osteoporotic; PECAM1 gene; Paralysed; Patients; Pharmaceutical Preparations; Play; Population; Postmenopausal Osteoporosis; Prevention; Protective Agents; Rattus; Reporting; Risk; Rodent; Rodent Model; Role; Spinal cord injury; Spinal cord injury patients; Sprague-Dawley Rats; Staining method; Stains; Surface; Testing; Time; Training; Vascular Endothelial Growth Factors; Vascular blood supply; Veterans; Work; Yarrow; bisphosphonate; bone; bone loss; bone mass; femoral artery; improved; in vivo; innovation; limb bone; male; microCT; mouse model; novel therapeutics; pre-clinical; preclinical study; prevent; research study; sham surgery; skeletal

Bone loss following spinal cord injury (SCI) is an important problem in the Veteran population. Bisphosphonates are currently the frontline therapy for postmenopausal osteoporosis, but do not restore bone in patients following SCI. Thus there is a need for new therapies. Bone loss following SCI results in part from disuse, but may also result from a variety of other mechanisms including the loss of blood supply to the bone. Ding et al. have shown in a mouse model, that SCI causes a dramatic loss of bone vascular volume. We propose a preclinical rat study to determine 1) whether reduced bone blood and reduced vascular volume play a role in bone loss following SCI and 2) whether bone loss can be prevented by administration of tetramethylpyrazine (TMP) alone or in combination with passive motorized bicycle training. Our proposed study is innovative because 1) we will study bone blood supply comprehensively (i.e. we will measure both blood flow and vascular volume), 2) we will determine whether bone blood supply is compromised before SCI-induced loss of bone mineral and 3) we will test strategies to prevent both loss of bone blood supply and loss of bone mineral following SCI. Our study has 2 specific aims. Aim 1: Determine whether severe SCI causes early deficits in bone blood flow and bone vascularity and whether the time course of these changes precedes or matches that of cancellous bone loss. Hypothesis 1: SCI will cause significant loss of femoral blood flow (via in vivo microsphere administration) and femoral vascular volume (via micro CT of perfused vasculature) that will precede or accompany the reduced cancellous bone volume, reduced trabecular number, and increased osteoclast surface that we have previously reported to occur following SCI. Aim 2: Determine whether SCI-induced deficits in bone blood flow, bone vascularity, and cancellous bone volume are prevented by TMP administration or by motorized bicycle training, alone or in combination. Hypothesis 2: Administration of TMP will prevent SCI-induced changes in vasculature and cancellous bone by protecting bone blood flow. Motorized bicycle exercise will also partially protect bone as we have previously observed. We predict that the greatest protection will occur in the group receiving combined TMP and bicycle straining. Male Sprague-Dawley rats will receive a severe contusion injury vs. sham surgery. Over 4 weeks, we will assess bone blood flow in femurs by administration of microspheres to conscious rats via the femoral artery. We will also assess vascular volume in decalcified femurs of rats perfused with vascular microfil at the time of sacrifice. We will perform comprehensive analysis of cancellous bone morphology in distal femur, employing both micro CT and histomorphometry. In addition, fluorochromes will be administered to live animals to allow for histological assessment of osteoblast and osteoclast surfaces. We will administer multi- modal therapy (TMP with or without passive motorized bicycle training) to prevent bone loss following SCI. TMP is an herb-derived agent that is approved as a food additive and has been shown to protect bone following glucocorticoid administration. Our preliminary data shows that passive bicycle training partially protects bone following SCI.

脊髓损伤（SCI）后的骨质流失是退伍军人群体中的一个重要问题。 双磷酸盐目前是绝经后骨质疏松症的一线治疗方法，但不能恢复 SCI 后患者的骨骼。因此需要新的疗法。 SCI 后骨质流失导致 部分是由于废用造成的，但也可能是由各种其他机制造成的，包括血液供应丧失 骨头。丁等人。在小鼠模型中表明，SCI 会导致骨血管急剧丧失 体积。我们提出了一项临床前大鼠研究，以确定 1) 骨血是否减少并减少 血管容量在 SCI 后骨质流失中发挥作用，2) 是否可以通过以下方式预防骨质流失 单独施用四甲基吡嗪（TMP）或与被动机动自行车训练相结合。 我们提出的研究具有创新性，因为1）我们将全面研究骨血液供应（即我们将 测量血流量和血管容量），2）我们将确定骨血液供应是否正常 在 SCI 引起的骨矿物质损失之前受到损害，并且 3）我们将测试防止骨矿物质损失的策略 SCI 后骨血液供应和骨矿物质损失。我们的研究有两个具体目标。 目标 1：确定严重 SCI 是否会导致骨血流和骨血管供应的早期缺陷以及 这些变化的时间进程是否先于或与松质骨丢失的时间进程相匹配。假设1： SCI 将导致股骨血流显着损失（通过体内微球给药）和股骨 松质纤维减少之前或伴随的血管容量（通过灌注脉管系统的显微 CT） 我们之前报道过的骨量、小梁数量减少和破骨细胞表面增加 发生在 SCI 之后。 目标 2：确定 SCI 是否会引起骨血流、骨血管分布和松质骨缺陷 通过单独或组合使用 TMP 给药或机动自行车训练来防止体积增大。 假设 2：服用 TMP 将通过以下方式预防 SCI 引起的脉管系统和松质骨的变化： 保护骨血流量。正如我们之前所提到的，电动自行车锻炼也将部分保护骨骼 观察到。我们预测，接受 TMP 和自行车联合治疗的组将获得最大的保护 使劲。 与假手术相比，雄性斯普拉格-道利大鼠将受到严重挫伤。 4周多的时间里，我们 将通过股骨向有意识的大鼠施用微球来评估股骨中的骨血流量 动脉。我们还将评估用血管微丝灌注的大鼠脱钙股骨的血管体积 牺牲的时刻。我们将对股骨远端松质骨形态进行全面分析， 同时采用显微 CT 和组织形态计量学。此外，荧光染料将被施用到活体上 动物以允许对成骨细胞和破骨细胞表面进行组织学评估。我们将管理多 模式治疗（TMP，有或没有被动机动自行车训练），以防止 SCI 后骨质流失。 TMP 是一种草药衍生剂，被批准作为食品添加剂，并已被证明可以保护骨骼 给予糖皮质激素后。我们的初步数据显示被动自行车训练部分 保护 SCI 后的骨骼。