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: 8678065
• 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/8678065
• 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.

描述： 目前，尚无实用的治疗方法可以预防 SCI 患者骨质流失或促进骨骼重建。 Wnt 抑制剂（例如主要由骨细胞产生的硬化蛋白）对骨中 Wnt 信号传导的调节对于骨质疏松症的发病机制至关重要，尤其是因废用所致的骨质疏松症。在最近的 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矿物质密度 (BMD)。在一项初步研究中，我们发现，当 SCI 后 7 天开始服用并持续 7 周时，Scl-Ab 几乎完全阻止了 SCI 引起的 BMD 降低，并部分保留了小梁微结构。 Scl-Ab 还增加离体培养的骨髓祖细胞的成骨细胞生成并减少破骨细胞生成。因此，我们提出了以下问题：1）SCI后立即开始施用Scl-Ab是否能完全防止骨质流失？ 2) SCI后28天开始施用Scl-Ab是否能够增加骨量和强度，此时骨量已经明显流失。在这些概念验证研究中，Scl-Ab 将以 25 毫克/公斤/周的剂量给药，正如我们在前期工作中所做的那样。此外，还提出了一项初步研究，以探索施用较低、临床相关剂量的 Scl-Ab 对减少 SCI 相关骨丢失的效果。 一般而言，机械卸载引起的骨质流失的机制，尤其是 SCI 后的机制，目前仍知之甚少。骨细胞占所有骨细胞的 90% 至 95%，它们被认为是通过将机械信号转换为化学信号来调节破骨细胞和成骨细胞活性的骨重塑的协调者。重要的是，我们发现卵巢切除 (OVX) 大鼠的骨细胞形态异常，并且用 Scl-Ab 治疗 OVX 大大改善了骨细胞形态。因此，我们假设骨细胞的病理变化可能是 SCI 动物骨质流失的主要原因，并且通过 Scl-Ab 恢复骨细胞结构和功能将挽救 SCI 相关的骨质流失。为了解决这些问题和假设，提出了三个具体目标： 目标 1. 进行概念验证研究，以评估 Scl-Ab 在 SCI 后保持骨完整性的能力。目标 1a) 测试在 SCI 时启动 Scl-Ab 是否可以完全防止 SCI 引起的骨质流失。 Scl-Ab 25 mg/kg/周将在 SCI 后一小时内开始，并持续 2 个月。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学标记物，以及骨髓祖细胞的成骨细胞生成和破骨细胞生成。目标 1b) 评估 SCI 后 1 个月开始使用 Scl-Ab 逆转骨质流失的能力。 Scl-Ab 将在 SCI 后 28 天开始，并持续 1、4 或 8 周。 目标 2. 进行一项初步研究，以测试较低剂量的 Scl-Ab 减少 SCI 相关骨丢失的能力。类似的 将采用实现拟议目标 1a 的方法，但 Scl-Ab 将以两个较低剂量（3 或 9 mg/kg/月）施用。这项工作将为临床护理以最低成本维持治疗效果的 Scl-Ab 最低有效剂量提供初步见解。 目标 3. 测试骨细胞功能受损是否是 SCI 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 挽救骨丢失的机制。 Aim 1 研究中动物骨细胞的功能特性将通过分析以下内容来表征：i) 骨细胞形态； ii) 骨细胞数量和细胞凋亡； iii) 骨细胞基因和蛋白质表达； iv) 参与骨力传导途径的关键因素。 上述研究将是第一个系统评价Scl-Ab预防或逆转SCI后骨丢失的功效并探讨Scl-Ab如何调节骨细胞功能的研究。如果结果符合预期，Scl-Ab 可能会为改善 SCI 患者骨骼健康的新型有效药物带来第一个希望。