ES and Androgens in Bone Loss after SCI: Synergistic Effects and Mechanisms

ES 和雄激素在 SCI 后骨丢失中的作用：协同效应和机制

• 批准号: 8399468
• 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: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8399468
• 关键词: Acute; Address; Affect; Anabolic steroids; Androgens; Biological; Body Weight; Bone Marrow; Bone Marrow Cells; Bone Resorption; Cells; Chronic; Clinical; DNA; Data; Development; Differentiation Antigens; Differentiation Inhibitor; Electric Stimulation; Engineering; Fracture; Future; Gene Expression; Genes; Health Care Costs; Hip Fractures; Hospitalization; Hour; Individual; Intervention; Knowledge; Link; Measures; Mechanics; Metabolic; Microarray Analysis; Modeling; Molecular; Molecular Profiling; Morbidity - disease rate; Motor; Musculoskeletal; Nandrolone; Nerve; Osteoblasts; Osteoclasts; Osteogenesis; Paralysed; Pathological fracture; Persons; Property; Quality of life; Rattus; Reporting; Role; Signal Transduction; Spinal cord injury; Testing; Testosterone; Therapeutic; Translating; Tumor necrosis factor receptor 11b; United States; Up-Regulation; Veterans; Weight-Bearing state; bone; bone cell; bone health; bone loss; bone mass; bone metabolism; bone preservation; cDNA Arrays; case finding; clinical care; cost; improved; inhibitor/antagonist; innovation; osteoblast differentiation; osteoclastogenesis; prevent; protective effect; public health relevance; receptor; steroid hormone

DESCRIPTION (provided by applicant): Spinal cord injury (SCI) causes severe bone loss which may result in pathologic fractures and, consequently, increased morbidity and health care costs. To date, the most effective strategies for preserving or restoring bone after SCI have utilized electrical stimulation (ES)-induced musculoskeletal loading. One critical question is whether the beneficial effects of ES reflect a decrease in the elevated rate of bone resorption, increased formation of new bone, or both. Answers to these questions are likely to guide the development of future strategies to minimize bone loss after SCI by identifying those components of bone metabolism that are not optimally stimulated by ES and might therefore be targets for additional types of intervention. Our preliminary data indicate that one week of reloading of bone after SCI by ES reduced bone resorptive activity through the inhibition of osteoclastogenesis and osteoclast activity in a rat model of SCI. Importantly, ES reversed SCI-induced upregulation of the expression in osteoblasts of the Wnt inhibitors (DKK1, sFRP2 and SOST) and increased expression in these cells of the Wnt-responsive gene osteoprotegerin (OPG), an inhibitor of the differentiation and activity of osteoclasts. SCI related-bone loss may be worsened by reduced circulating levels of testosterone because this steroid hormone has anabolic actions on bone and its levels are commonly reduced after SCI. Recently, we observed that nandrolone, an anabolic steroid, reduced bone loss after paralysis due to SCI. Interestingly, nandrolone increased the expression of OPG, Runx2 and LRP5 in bone marrow-derived osteoblasts from SCI rats. LRP5 is a Wnt co-receptor closely linked to the control of bone mass, and Runx2 is another Wnt-responsive gene, and is involved in osteoblast differentiation. These findings suggest that one effect of nandrolone in unloaded bone is to stimulate Wnt signaling in osteoblasts and that Wnt signaling explains at least some of the protective effects of nandrolone on bone after SCI. The central hypotheses suggested by our findings are: 1) ES effects on bone are due to a decrease in the elevated rate of bone resorption and increased formation of new bone; 2) anabolic steroids will provide additional or synergistic benefits to SCI-related bone loss when applied in conjunction with ES. If this is the case, these findings would be readily translated to clinical cae, and would provide an innovative therapeutic strategy for the marked loss of bone following SCI. As such, the following specific aims are proposed: Specific Aim 1. To determine how ES alters the rates of bone formation and resorption and the properties of bone cells, and to characterize the effects of ES on bone mass. We will determine how longer or higher intensity of ES (i.e., 3 months for one hour a day or 1 month for 3 hours a day) alters BMD and BMC, and both metabolic and histomorphometric measures of bone resorption and bone formation. We will also test how longer periods or higher intensity of ES alter numbers of osteoclasts and osteoblasts in cultures of bone marrow cells and examine changes in expression in these cells of genes for their differentiation and activity. Specific Aim 2. To determine whether a combination of ES and an androgen will reduce SCI- related bone loss to a greater extent than either ES or androgen alone. Nandrolone will be administered with or without concurrent ES. We will compare the effects on bone and bone cells of nandrolone combined with ES with the effects observed for ES or nandrolone alone. The possible role for other cellular and molecular mechanisms by which SCI-related bone loss is reduced by ES alone or nandrolone alone or in combination will be studied using DNA microarry analysis. PUBLIC HEALTH RELEVANCE: Spinal cord injury (SCI) affects more than 40,000 veterans. The dramatic loss of bone mass and structural integrity that follows SCI is a significant cause of spontaneous fractures and morbidity The weakened bones of persons with SCI may not support the body's weight during ambulation, thus limiting the potential benefit of neurorepair. At present, there is no practical treatment tha is clinically available to delay or prevent bone loss after acute SCI, or to promote rebuilding of bone in individuals with chronic SCI. Therefore, any intervention that preserves bone after acute SCI, or rebuilds bone in chronic SCI, would have a tremendous long-term potential to facilitate weight bearing when biological or engineering interventions which permit ambulation to become a reality, and thus to improve quality of life. The current proposal will significantly enhance our knowledge as to how to improve bone health after SCI.

描述（由申请人提供）： 脊髓损伤 (SCI) 会导致严重的骨质流失，从而可能导致病理性骨折，从而增加发病率和医疗费用。迄今为止，SCI 后保留或恢复骨骼的最有效策略是利用电刺激 (ES) 诱导的肌肉骨骼负荷。一个关键问题是 ES 的有益作用是否反映了骨吸收率升高、新骨形成增加或两者兼而有之。这些问题的答案可能会指导未来策略的制定，通过识别 ES 不能最佳刺激的骨代谢成分，从而最大限度地减少 SCI 后的骨质流失，因此可能成为其他类型干预的目标。我们的初步数据表明，在 SCI 大鼠模型中，SCI 后用 ES 进行骨再装载一周，可通过抑制破骨细胞生成和破骨细胞活性来降低骨吸收活性。重要的是，ES 逆转了 SCI 诱导的成骨细胞中 Wnt 抑制剂（DKK1、sFRP2 和 SOST）表达的上调，并增加了这些细胞中 Wnt 反应基因骨保护素（OPG）的表达，OPG 是破骨细胞分化和活性的抑制剂。 睾酮循环水平降低可能会加剧 SCI 相关的骨质流失，因为这种类固醇激素对骨骼具有合成代谢作用，并且其水平在 SCI 后通常会降低。最近，我们观察到诺龙（一种合成代谢类固醇）可减少 SCI 导致的瘫痪后的骨质流失。有趣的是，诺龙增加了 SCI 大鼠骨髓来源的成骨细胞中 OPG、Runx2 和 LRP5 的表达。 LRP5是与骨量控制密切相关的Wnt辅助受体，Runx2是另一个Wnt反应基因，参与成骨细胞分化。这些发现表明，诺龙对空载骨的作用之一是刺激成骨细胞中的 Wnt 信号传导，并且 Wnt 信号传导至少解释了诺龙对 SCI 后骨的一些保护作用。 我们的研究结果提出的中心假设是：1）ES 对骨的影响是由于骨吸收率升高和新骨形成增加所致； 2) 与 ES 联合使用时，合成代谢类固醇将为 SCI 相关骨质流失提供额外或协同益处。如果是这样的话，这些发现将很容易转化为临床治疗，并将为 SCI 后明显的骨质流失提供创新的治疗策略。因此，提出以下具体目标： 具体目标 1. 确定 ES 如何改变骨形成和吸收速率以及骨细胞的特性，并表征 ES 对骨量的影响。我们将确定更长或更高强度的 ES（即 3 个月每天 1 小时或 1 个月每天 3 小时）如何改变 BMD 和 BMC，以及骨吸收和骨形成的代谢和组织形态测量。我们还将测试较长时间或较高强度的 ES 如何改变骨髓细胞培养物中破骨细胞和成骨细胞的数量，并检查这些细胞中基因表达的变化，以了解其分化和活性。 具体目标 2. 确定 ES 和雄激素的组合是否会比单独使用 ES 或雄激素更大程度地减少 SCI 相关的骨丢失。诺龙将与或不与 ES 同时施用。我们将比较诺龙联合 ES 与单独使用 ES 或诺龙对骨和骨细胞的影响。将使用 DNA 微阵列分析来研究单独使用 ES 或单独使用诺龙或联合使用诺龙来减少 SCI 相关骨质流失的其他细胞和分子机制的可能作用。 公共卫生相关性： 脊髓损伤 (SCI) 影响着超过 40,000 名退伍军人。 SCI 后骨量和结构完整性的急剧丧失是自发性骨折和发病的重要原因。SCI 患者骨骼脆弱，在行走过程中可能无法支撑身体的重量，从而限制了神经修复的潜在益处。目前，临床上尚无实用的治疗方法可以延迟或预防急性 SCI 后的骨丢失，或促进慢性 SCI 个体的骨重建。因此，当允许行走的生物或工程干预成为现实时，任何在急性 SCI 后保留骨骼或在慢性 SCI 中重建骨骼的干预措施都将具有促进负重的巨大长期潜力，从而提高生活质量。当前的提案将显着增强我们的 有关如何在 SCI 后改善骨骼健康的知识。