Interventions and Mechanisms of Disuse Osteopenia

描述(由申请人提供)： 骨骼对机械负荷的适应会导致患有暂时性瘫痪、虚弱或卧床休息的患者迅速失去显著的骨量、密度和强度，导致骨量减少/骨质疏松，并增加脆性骨折的风险。旨在防止废用引起的骨丢失或增强对增加的负荷的合成代谢反应的治疗方法将降低骨折发生率。然而，调控这些过程的细胞和分子机制却知之甚少。目前的建议将调查Sirt1在废用引起的骨丢失和增加负荷的骨骼适应中的作用。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也控制着许多其他蛋白质的活性，包括连环蛋白，一种骨骼适应负荷的中介。初步研究表明，Sirtuin1蛋白在成骨细胞、骨细胞和破骨细胞中均有表达。成骨细胞和成骨细胞中SIRT1的条件性缺失 小鼠的骨细胞在4个月龄时会导致骨量/体积低的表型。一项单轴胫骨负荷研究令人惊讶地显示，Sirt10b-/-小鼠的长骨对负荷增加的合成代谢效应高度敏感。更多数据显示，删除 Of Sirt1抑制Wnt信号，从而抑制成熟成骨细胞的成骨活性。因此，这一建议的假设是，Sirt1通常通过允许激活成熟成骨细胞中规范的Wnt信号来抑制骨骼对增加的负荷的反应，并促进废用性骨量减少。这一假设将在以下三个目标中进行探索。目的1-确定成骨细胞和/或骨细胞中Sirt1的缺失是否在机械负荷增加时促进骨形成和Wnt信号转导。目的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量减少，并促进废用性骨的恢复。目的3-确定Sirt1在成骨细胞和骨细胞中对Wnt信号转导和β-catenin转录活性的影响，并确定成骨细胞中其他Sirt1底物。这些研究将确定成骨细胞和/或骨细胞中的Sirt1及其底物是否为废用性骨量减少和潜在的各种其他原因导致的骨丢失的新干预措施的潜在治疗靶点。

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.