Interventions and Mechanisms of Disuse Osteopenia

废用性骨质减少的干预措施和机制

• 批准号: 8667309
• 负责人: Daniel S Perrien
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-01-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8667309
• 关键词: Acetylation; Acute; Age; Age-Months; Anabolism; Bed rest; Bone Density; Bone Formation Inhibition; Chronic Disease; Collagen Type I; Data; Deacetylase; Development; Differentiation Inhibitor; Disease; Drosophila genus; Drug Targeting; Dsh protein; Failure; Foundations; Fracture; Future; Gene Targeting; Hindlimb Suspension; Histone Deacetylase; Hypersensitivity; Injury; Intervention; Lead; Life; Limb structure; Liquid substance; Measures; Mechanics; Mediator of activation protein; Molecular; Mus; Osteoblasts; Osteoclasts; Osteocytes; Osteogenesis; Osteopenia; Osteoporosis; Paralysed; Pathological fracture; Patients; Phenotype; Pilot Projects; Population; Prevention; Process; Proteins; Recovery; Risk; Role; Signal Transduction; Staging; Suspension substance; Suspensions; System; Testing; Veterans; Work; Yeasts; age effect; aging gene; anti aging; beta catenin; bone; bone loss; bone mass; density; disability; economic impact; improved; in vivo; innovation; long bone; mineralization; new therapeutic target; novel; novel therapeutics; osteoblast differentiation; prevent; promoter; public health relevance; recombinase; response; skeletal; tibia

DESCRIPTION (provided by applicant): Skeletal adaptation to mechanical load causes patients subject to temporary paralysis, debilitation, or bedrest to rapidly lose significant bone mass, density, and strength leading to osteopenia/osteoporosis and an increased risk of fragility fractures. Therapies aimed at preventing disuse-induced bone loss or enhancing the anabolic response to increased load would reduce fracture rates. However, the cellular and molecular mechanisms regulating these processes are poorly understood. The current proposal will investigate the contribution of Sirt1 in disuse-induced bone loss and the skeletal adaptation to increased loading. The sirt1 gene product, Sirtuin 1, is a histone deacetylase (HDAC) that has been termed an "anti-aging" gene. However, Sirt1 also controls the activity of many other proteins including ¿- catenin, a mediator of skeletal adaptation to load. Preliminary data demonstrate that Sirtuin 1 protein is expressed in osteoblasts, osteocytes, and osteoclasts. Conditional deletion of sirt1 in both osteoblasts and osteocytes in mice leads to a low bone mass/volume phenotype by 4 months of age. A uniaxial tibial loading study surprisingly revealed that the long bones of Sirt1Ob-/- mice were hypersensitive to the anabolic effect of increased loading. Additional data revealed that deletion of Sirt1 suppresses Wnt signaling, which inhibits the bone forming activity of mature osteoblasts. Hence the hypothesis for this proposal is that Sirt1 normally suppresses the bone response to increased loading and promotes disuse osteopenia by permitting activation of canonical Wnt signaling in mature osteoblasts. This hypothesis will be explored in the following three aims. Aim 1 - Determine whether deletion of Sirt1 in osteoblasts and/or osteocytes enhances bone formation and Wnt signaling in response to increased mechanical loading. Aim 2 - Determine whether deletion of Sirt1 in osteoblasts and/or osteocytes accelerates disuse osteopenia and enhances the recovery of bone following disuse. Aim 3 - Determine the effects of Sirt1 on Wnt signaling and ¿-catenin transcriptional activity in osteoblasts and osteocytes and identify additional Sirt1 substrates in osteoblasts. These studies will determine whether Sirt1 and its substrates in osteoblasts and/or osteocytes are potential therapeutic targets for novel interventions for disuse osteopenia and, potentially, bone loss from a variety of other causes.

描述（由申请人提供）： 骨骼对机械负荷的适应会导致暂时性瘫痪、虚弱或卧床休息的患者迅速丧失大量骨量、密度和强度，导致骨质减少/骨质疏松症和脆性骨折的风险增加。旨在预防废用性骨质流失或增强对增加负荷的合成代谢反应的治疗将降低骨折率。然而，人们对调节这些过程的细胞和分子机制知之甚少。 目前的提案将研究 Sirt1 在废用性骨质流失中的作用以及骨骼对负荷增加的适应。 Sirt1 基因产物 Sirtuin 1 是一种组蛋白脱乙酰酶 (HDAC)，被称为“抗衰老”基因。然而，Sirt1 还控制许多其他蛋白质的活性，包括 β-连环蛋白（骨骼适应负荷的介质）。初步数据表明 Sirtuin 1 蛋白在成骨细胞、骨细胞和破骨细胞中表达。在成骨细胞和成骨细胞中条件性删除sirt1 小鼠的骨细胞在 4 个月大时会导致低骨量/骨量表型。一项单轴胫骨负荷研究令人惊讶地发现，Sirt1Ob-/- 小鼠的长骨对增加负荷的合成代谢效应非常敏感。附加数据显示删除 Sirt1 抑制 Wnt 信号传导，从而抑制成熟成骨细胞的骨形成活性。因此，该提议的假设是，Sirt1 通常会抑制骨对负荷增加的反应，并通过激活成熟成骨细胞中的经典 Wnt 信号来促进废用性骨质减少。该假设将在以下三个目标中进行探讨。 目标 1 - 确定成骨细胞和/或骨细胞中 Sirt1 的缺失是否会增强骨形成和 Wnt 信号传导以响应增加的机械负荷。 目标 2 - 确定成骨细胞和/或骨细胞中 Sirt1 的缺失是否会加速废用性骨质减少并增强废用后骨的恢复。 目标 3 - 确定 Sirt1 对成骨细胞和骨细胞中 Wnt 信号传导和 ¿-catenin 转录活性的影响，并鉴定成骨细胞中其他 Sirt1 底物。 这些研究将确定 Sirt1 及其在成骨细胞和/或骨细胞中的底物是否是针对废用性骨质减少以及各种其他原因引起的骨质流失的新型干预措施的潜在治疗靶点。