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）后的骨丢失是退伍军人群体中的一个重要问题。 双膦酸盐目前是绝经后骨质疏松症的一线治疗，但不能恢复 脊髓损伤患者的骨骼。因此，需要新的治疗方法。脊髓损伤后骨丢失导致 部分原因是废用，但也可能是由于各种其他机制，包括血液供应的损失， 骨头Ding等人在小鼠模型中显示，SCI导致骨血管的急剧损失， 音量.我们提出了一个临床前大鼠研究，以确定1）是否减少骨血和减少 血管体积在SCI后骨丢失中起作用，以及2）骨丢失是否可以通过 单独或与被动机动自行车训练组合施用川芎嗪（TMP）。 我们提出的研究是创新的，因为1）我们将全面研究骨血供（即，我们将 测量血流量和血管体积），2）我们将确定骨骼血液供应是否 在SCI诱导的骨矿物质损失之前受到损害，3）我们将测试防止骨矿物质损失的策略 脊髓损伤后的骨血供和骨矿物质丢失。我们的研究有两个具体目标。 目的1：确定严重SCI是否会导致骨血流和骨血管的早期缺陷， 这些变化的时间进程是否先于或匹配松质骨丢失。假设1： SCI将导致股动脉血流（通过体内微球给药）和股动脉血流（通过体内微球给药）的显著损失。 血管体积（通过灌注血管系统的微CT）将先于或伴随减少的松质骨 骨体积，减少骨小梁数量，增加破骨细胞表面，我们以前曾报道 发生在SCI之后。 目的2：确定SCI是否引起骨血流量、骨血管和松质骨的缺陷 通过单独或联合施用TMP或通过机动自行车训练来预防。 假设2：TMP给药将通过以下方式预防SCI诱导的血管和松质骨变化： 保护骨骼血液流动。摩托自行车运动也将部分保护骨，因为我们以前有 观察我们预测，最大的保护将发生在组接受联合TMP和自行车 紧张 雄性Sprague-Dawley大鼠将接受严重挫伤与假手术。4个多星期，我们 将通过经股骨向清醒的大鼠施用微球来评估股骨中的骨血流 动脉我们还将评估用血管微纤维灌注的大鼠脱钙股骨中的血管体积， 牺牲的时刻。我们将对股骨远端松质骨形态进行综合分析， 使用显微CT和组织形态测量法。此外，荧光染料将被管理， 动物以允许对成骨细胞和破骨细胞表面进行组织学评估。我们将管理多个- 模式治疗（TMP+或不+被动机动自行车训练），以预防SCI后骨丢失。 TMP是一种草药衍生剂，已被批准作为食品添加剂，并已被证明可以保护骨骼 糖皮质激素给药后。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。