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）： 对机械负荷的骨骼适应会导致患者暂时瘫痪，虚弱或卧室迅速失去明显的骨骼质量，密度和强度，导致骨质减少症/骨质疏松症以及增加脆性分数的风险增加。旨在防止废弃诱导的骨质流失或增强对负载增加的合成代谢反应的疗法将降低断裂率。然而，调节这些过程的细胞和分子机制知之甚少。当前的提案将研究SIRT1在废弃诱导的骨质流失方面的贡献以及对增加负荷的骨骼适应性。 SIRT1基因产物Sirtuin 1是一种组蛋白脱乙酰基酶（HDAC），称为“抗衰老”基因。但是，SIRT1还控制着许多其他蛋白质的活性，包括 - catenin，是骨骼适应性载荷的介体。初步数据表明，Sirtuin 1蛋白在成骨细胞，骨细胞和骨细胞中表达。在成骨细胞和 小鼠的骨细胞导致骨质量/体积表型低4个月。一项单轴胫骨负荷研究令人惊讶地表明，SIRT1OB - / - 小鼠的长骨对增加负载的合成代谢作用过敏。其他数据显示删除 SIRT1抑制Wnt信号传导，这抑制了成熟成骨细胞的骨形成活性。因此，该提议的假设是SIRT1通常抑制骨头对增加负荷的反应，并通过允许在成熟成骨细胞中激活规范的Wnt信号传导来促进骨质减少症。该假设将在以下三个目标中进行探讨。目标1-确定成骨细胞中SIRT1的缺失和/或骨细胞是否会增强骨形成和Wnt信号传导，以响应增加机械负荷。 AIM 2-确定在成骨细胞和/或骨细胞中SIRT1的缺失是否加速消除骨质骨减少症并增强废弃后骨骼的恢复。 AIM 3-确定SIRT1对成骨细胞和成骨细胞中Wnt信号传导和 - 帕宁蛋白转录活性的影响，并在成骨细胞中识别其他SIRT1底物。这些研究将确定成骨细胞和/或骨细胞中的SIRT1及其底物是否是用于废弃骨质减少症的新干预措施的潜在治疗靶标，并且可能导致各种其他原因造成骨骼流失。