Interventions and Mechanisms of Disuse Osteopenia

描述（由申请人提供）： 骨骼对机械负荷的适应导致患者暂时性瘫痪、虚弱或卧床休息，迅速失去大量骨量、密度和强度，导致骨质减少/骨质疏松症，并增加脆性骨折的风险。旨在预防废用性骨丢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，调控这些过程的细胞和分子机制知之甚少。 目前的建议将调查Sirt 1在废用性骨丢失和骨骼适应增加负荷的贡献。sirt 1基因产物Sirtuin 1是一种组蛋白去乙酰化酶（HDAC），被称为“抗衰老”基因。然而，Sirt 1还控制许多其他蛋白质的活性，包括骨骼适应负荷的介导物-连环蛋白。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。成骨细胞和成骨细胞中sirt 1的条件性缺失 小鼠中的骨细胞导致4月龄时的低骨量/体积表型。一项单轴胫骨负荷研究令人惊讶地发现，Sirt 1 Ob-/-小鼠的长骨对增加负荷的合成代谢作用高度敏感。其他数据显示， Sirt 1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，该建议的假设是，Sirt 1通常抑制骨对增加的负荷的反应，并通过允许成熟成骨细胞中经典Wnt信号的激活来促进废用性骨质减少。这一假设将在以下三个目标中进行探讨。 目的1 -确定成骨细胞和/或骨细胞中Sirt 1的缺失是否会增强骨形成和Wnt信号传导，以响应机械负荷的增加。 目的2 -确定成骨细胞和/或骨细胞中Sirt 1的缺失是否加速废用性骨质减少并增强废用后骨的恢复。 目的3 -确定Sirt 1对成骨细胞和骨细胞中Wnt信号传导和<$-连环蛋白转录活性的影响，并鉴定成骨细胞中的其他Sirt 1底物。 这些研究将确定成骨细胞和/或骨细胞中的Sirt 1及其底物是否是废用性骨质减少和潜在的各种其他原因引起的骨丢失的新型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.