Role Of Bone Blood Flow In Bone Loss Following SCI

脊髓损伤(SCI)后骨丢失是退伍军人面临的一个重要问题。 双膦酸盐是目前治疗绝经后骨质疏松症的一线药物，但不能恢复 脊髓损伤后患者的骨骼。因此，需要新的治疗方法。脊髓损伤后的骨丢失导致 部分原因是停用，但也可能是各种其他机制造成的，包括失去对 骨头。丁等人已经在老鼠模型中表明，脊髓损伤会导致骨血管的戏剧性损失 音量。我们提出了一项临床前大鼠研究，以确定1)减少骨血和减少 血管容量在脊髓损伤后骨丢失中的作用以及2)骨丢失是否可以通过 单独或与被动机动自行车训练联合使用川芎嗪(TMP)。 我们提议的研究是创新的，因为1)我们将全面研究骨骼血液供应(即我们将 同时测量血流量和血管容量)，2)我们将确定骨骼血供是否 在脊髓损伤引起的骨矿物质丢失之前妥协和3)我们将测试防止两者丢失的策略 脊髓损伤后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：确定严重脊髓损伤是否会导致早期骨血流量和骨血管功能障碍 这些变化的时间进程是否先于或匹配松质骨丢失。假设1： 脊髓损伤将导致股骨血流的显著损失(通过体内微球注射)和股骨 在减少的松质骨之前或伴随减少的血管体积(通过灌流血管的微型CT) 骨体积减少，骨小梁数量减少，破骨细胞表面增加，这是我们以前报道过的 发生在脊髓损伤之后。 目的2：确定脊髓损伤是否导致骨血流量、骨血管和松质骨的不足 通过单独或联合使用TMP管理或机动自行车训练来防止音量增加。 假设2：TMP可通过以下途径预防脊髓损伤引起的血管和松质骨改变 保护骨骼血液流动。机动自行车运动也会像我们以前那样部分保护骨骼 观察到的。我们预测，最大的保护将发生在接受TMP和自行车联合治疗的组 太紧张了。 雄性SD大鼠将接受严重挫伤，而不是假手术。在超过四周的时间里，我们 将通过股骨给清醒的大鼠注射微球来评估股骨的骨血流量 动脉。我们还将评估血管微球灌注大鼠脱钙股骨的血管体积。 牺牲的时刻。我们将对股骨远端的松质骨形态进行全面的分析， 采用显微CT和组织形态计量学方法。此外，荧光染料还将用于活体 允许对成骨细胞和破骨细胞表面进行组织学评估的动物。我们将管理多个 预防脊髓损伤后骨丢失的模式疗法(TMP加或不加被动机动自行车训练)。 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 在使用糖皮质激素后。我们的初步数据显示，被动自行车训练部分 保护脊髓损伤后的骨骼。

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.