Sclerostin Antagonism and the Osteocytes Role Prevention of Bone Loss after SCI

硬化素拮抗剂和骨细胞在预防 SCI 后骨丢失的作用

• 批准号: 9110747
• 负责人: Weiping Qin
• 金额: --
• 依托单位: JAMES J PETERS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-05-01 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9110747
• 关键词: Address; Animal Model; Animals; Antibodies; Apoptosis; Area; Biology; Blood; Bone Density; Bone Marrow; Bone Marrow Cells; Bone Resorption; Bone remodeling; Caring; Chemicals; Clinical; Clinical Investigator; Clinical Research; Clinical Trials; Data; Deterioration; Dinoprostone; Dose; Down-Regulation; Drug Industry; Fracture; Future; Gene Expression; Histology; Hour; Impairment; Individual; Injury; Intervention; Investigation; Knee; Marrow; Mechanics; Microscopy; Morbidity - disease rate; Morphology; Nitric Oxide; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis; Osteoporosis; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Phase; Pilot Projects; Postmenopause; Prevention; Property; Rattus; Reducing Agents; Regulation; Research Personnel; Risk; Role; Scanning; Scientist; Seasons; Signal Transduction; Site; Spinal Cord transection injury; Spinal cord injury; Spinal cord injury patients; Stem cells; Structure; TNFSF11 gene; Technology; Testing; Time; Treatment Efficacy; Veterans; Wistar Rats; Woman; Work; base; bone; bone cell; bone health; bone loss; bone mass; bone metabolism; bone strength; clinical application; clinically relevant; cost; dentin matrix protein 1; effective therapy; improved; inhibitor/antagonist; insight; male; medical complication; novel; osteoclastogenesis; pre-clinical; prevent; progenitor; protein expression; public health relevance; research study; response; restoration; success

DESCRIPTION: At present, there is no practical treatment to prevent bone loss, or promote rebuilding of bone, in individuals with SCI. Regulation of Wnt signaling in bone by Wnt inhibitors (e.g., sclerostin, which is mainly produced by osteocytes) is crucial in the pathogenesis of osteoporosis, especially that due to disuse. In a recent phase I and II clinical trial, anti-sclerostin antibodie (Scl-Ab) increased bone mineral density (BMD) in postmenopausal women. In a pilot study we found that, when begun at 7 days after SCI and administered for 7 weeks, Scl-Ab almost completely prevented the SCI-induced reduction of BMD and partially preserved trabecular microarchitecture. Scl-Ab also increased osteoblastogenesis and decreased osteoclastogenesis of ex vivo cultured bone marrow progenitor cells. Thus, we have asked the following questions: 1) Whether Scl-Ab will completely prevent bone loss when its administration is begun immediately after SCI; 2) whether Scl-Ab is able to increase bone mass and strength when its administration is begun 28 days after SCI, when significant bone loss has already developed. In these proof of concept studies, Scl-Ab will be administered at 25 mg/kg/week, as was done in our preliminary work. In addition, a pilot study is proposed to explore the effect of the administration of a lower, more clinically relevant dose of Scl-Ab to reduce SCI-related bone loss. The mechanisms underlying bone loss in response to mechanical unloading in general, and after SCI in particular, remain poorly understood. Osteocytes compose 90% to 95% of all bone cells, and they have been considered as an orchestrator of bone remodeling through regulation of osteoclast and osteoblast activity by transducing mechanical signals into chemical signals. Importantly, we showed abnormalities of osteocyte morphology in ovarectomized (OVX) rats, and treatment of OVX with Scl-Ab greatly improved osteocyte morphology. Thus, we hypothesize that pathological changes in osteocytes are likely a central cause for bone loss in SCI animals, and that restoration of osteocyte structure and function by Scl-Ab will rescue SCI related- bone loss. To address these questions and hypotheses three specific aims are proposed: Aim 1. To perform proof of concept studies to evaluate the ability of Scl-Ab to preserve bone integrity after SCI. Aim 1a) To test whether initiating Scl-Ab at the time of SCI protects completely against bone loss due to SCI. Scl-Ab at 25 mg/kg/week will begin within one hour after SCI and be continued for 2 months. The key endpoints to be determined will be bone mass, microarchitecture, strength, blood and histomorphometric markers for bone formation and resorption, and osteoblastogenesis and osteoclastogenesis of bone marrow progenitors. Aim 1b) To evaluate the ability of Scl-Ab to reverse bone loss when initiated 1 month after SCI. Scl-Ab will be initiated 28 days after SCI and continued for 1, 4 or 8 weeks. Aim 2. To conduct a pilot study to test the ability of lower doses of Scl-Ab to reduce SCI-related bone loss. A similar approach to that proposed Aim 1a will be employed, except that Scl-Ab will be administered at two lower doses (3 or 9 mg/kg/month). This work will provide initial insight as to the minimum effective dose of Scl-Ab capable of maintaining therapeutic efficacy at the lowest cost for clinica care. Aim 3. To test whether impairment of osteocyte function is one mechanism by which SCI causes bone loss, and whether restoration of normal osteocyte function is a mechanism by which Scl-Ab rescues such bone loss. The functional properties of osteocytes in animals from Aim 1 study will be characterized by analysis of: i) osteocyte morphology; ii) osteocyte number and apoptosis; iii) osteocytic gene and protein expression; and iv) key factors involved in bone mechanotransduction pathway. The above studies will be the first study to systematically evaluate the efficacy of Scl-Ab to prevent or reverse bone loss after SCI and to explore how Scl-Ab regulates osteocyte function. If the results are as expected, Scl-Ab might offer the first hope of a novel potent agent to improve bone health in SCI patients.

说明： 目前，还没有实用的治疗方法来预防脊髓损伤患者的骨丢失，或促进骨重建。Wnt抑制剂(如主要由骨细胞产生的硬化素)对骨骼中Wnt信号的调节在骨质疏松症的发病机制中是至关重要的，尤其是由于停用。在最近的一项I期和II期临床试验中，抗硬化素抗体(scl-Ab)增加了绝经后妇女的骨密度(BMD)。在一项先导性研究中，我们发现，在脊髓损伤后7天开始给药7周时，scl-Ab几乎完全阻止了脊髓损伤诱导的骨密度降低，并部分保留了骨小梁的微结构。SCL-Ab还可促进体外培养的骨髓前体细胞的成骨细胞生成，减少其破骨细胞生成。因此，我们提出了以下问题：1)SCL-Ab在脊髓损伤后立即开始给药是否能完全防止骨丢失；2)SCL-Ab在脊髓损伤后28天开始给药时是否能够增加骨量和强度，而此时已经出现了明显的骨丢失。在这些概念验证研究中，scl-Ab将以每周25 mg/kg的速度给予，就像我们在初步工作中所做的那样。此外，还建议进行一项先导性研究，以探索给予更低剂量、更具临床相关性的scl-Ab以减少脊髓损伤相关骨丢失的效果。一般情况下，尤其是在脊髓损伤后，机械卸载导致骨丢失的机制仍然知之甚少。骨细胞占所有骨细胞的90%~95%，它们通过将机械信号转化为化学信号来调节破骨细胞和成骨细胞的活动，从而被认为是骨重建的协调者。重要的是，我们发现去卵巢(OVX)大鼠骨细胞形态异常，用scl-Ab治疗OVX可显著改善骨细胞形态。因此，我们推测骨细胞的病理改变可能是脊髓损伤动物骨丢失的主要原因，通过scl-Ab恢复骨细胞的结构和功能将挽救脊髓损伤相关的骨丢失。为了解决这些问题和假设，本文提出了三个具体的目标：目的1.进行概念验证研究，以评估scl-Ab在脊髓损伤后保持骨完整性的能力。目的1a)检测脊髓损伤时应用scl-Ab是否能完全预防脊髓损伤所致的骨丢失。SCL-Ab25 mg/kg/周开始在脊髓损伤后1小时内开始，持续2个月。有待确定的关键终点是骨量、微结构、强度、血液和骨形成和吸收的组织形态计量学标记物，以及骨髓前体细胞的成骨和破骨分化。目的1b)评价SCL-Ab在脊髓损伤后1个月启动时逆转骨丢失的能力。SCL-Ab在脊髓损伤后28天开始免疫，持续1、4或8周。目的2.进行一项初步研究，以测试较低剂量的scl-Ab减少脊髓损伤相关骨丢失的能力。一种类似的 除了Scl-Ab将以两个较低的剂量(每月3或9 mg/kg/月)给药外，将采用与拟议的目标1a相一致的方法。这项工作将提供关于scl-Ab最小有效剂量的初步见解，该剂量能够以最低的临床护理成本维持治疗效果。目的3.检测脊髓损伤后骨细胞功能受损是否是导致骨丢失的机制之一，以及恢复正常骨细胞功能是否是scl-Ab挽救这种骨丢失的机制之一。AIM 1研究中的动物骨细胞的功能特性包括：1)骨细胞形态；2)骨细胞数量和细胞凋亡；3)骨细胞基因和蛋白表达；4)参与骨机械转导途径的关键因素。本研究首次系统评价了scl-Ab预防或逆转脊髓损伤后骨丢失的效果，并探讨了scl-Ab对骨细胞功能的调节作用。如果结果与预期一致，scl-Ab可能成为改善脊髓损伤患者骨健康的新型强效药物的第一个希望。