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.

脊髓损伤后的骨质流失（SCI）是退伍军人人口的重要问题。 双膦酸盐目前是绝经后骨质疏松症的一线疗法，但不要恢复 科学后患者的骨头。因此，需要新的疗法。 SCI后的骨质流失导致 一部分是由于废弃的部分，但也可能是由于多种其他机制而引起的，包括失血供应 骨头。丁等。在小鼠模型中显示的SCI导致骨血管的巨大损失 体积。我们提出了一项临床前大鼠研究以确定1）骨血的减少和减少。 血管量在SCI后和2）是否可以防止骨质流失在骨质流失中发挥作用 单独使用四甲基吡嗪（TMP）或与被动机动自行车训练结合使用。 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 测量血流和血管体积），2）我们将确定骨血供应是否为 在Sci诱导骨矿物质损失之前受到损害，3）我们将测试策略，以防止损失 骨血液供应和科幻后骨矿物质的丧失。我们的研究有2个具体目标。 目标1：确定严重的SCI是否会引起骨流量和骨血管性的早期缺陷 这些变化的时间过程是否在取消骨质流失之前或匹配。假设1： SCI将导致股骨血流的明显损失（通过体内微球给药）和股骨 血管体积（通过灌注脉管系统的微型CT）将在降低的取消量之前或伴随 骨骼体积，小梁数量减少以及我们先前报道的破骨细胞表面增加 在科幻之后发生。 目标2：确定SCI引起的骨血流，骨血管和取消骨的缺陷是否存在 TMP给药或单独或组合通过电动自行车训练来阻止体积。 假设2：施用TMP将防止SCI诱导的脉管系统变化和取消骨骼的变化 保护骨血流。像我们以前一样，电动自行车运动也将部分保护骨骼 观察到。我们预测，最大的保护将发生在接收TMP和自行车的组中 紧张。 男性Sprague-Dawley大鼠与假手术相比将受到严重的挫伤伤害。在四个星期中，我们 通过将微球施用到有意识的大鼠通过股骨来评估股骨的骨血流动 动脉。我们还将评估用血管灌注的大鼠脱钙化股骨的血管体积 牺牲的时间。我们将对股骨远端的取消骨形态进行全面分析， 同时采用微型CT和组织形态法。此外，将荧光染色体进行活机 动物可以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 模态疗法（带有或不具有被动机动自行车训练的TMP）可防止SCI后骨质流失。 TMP是一种草药衍生的剂，被批准为食物添加剂，并已被证明可以保护骨头 糖皮质激素给药后。我们的初步数据表明，被动自行车训练部分 保护科学后的骨头。