Molecular & cellular Mechanisms of Osteoporosis

描述（由申请人提供）：此续期申请的目标有三个方面。首先，我们计划利用我们在过去10年的成就，对其他器官或组织（如卵巢、骨髓、肾上腺）中与年龄相关的变化及其背后的细胞和分子机制的贡献进行全面的解剖，以与骨骼衰老本身的贡献相比，与年龄相关的骨量和强度损失。其次，我们将确定衰老对骨强度的各种定性方面的影响，包括微结构、疲劳损伤的患病率、骨转换和骨细胞数量。第三，我们将在导致年龄相关性骨质疏松症的特定致病因素的背景下，研究不同治疗方式对骨骼老化的相对疗效和机制的适宜性。为了实现该计划的目标，四个项目（由三个核心支持）将以专题和系统的方式解决密切相关的假设，这些假设将使用各种分子和细胞生物学方法以及正常衰老的C57BL/6小鼠和其他几种转基因和敲除小鼠进行测试。在项目1中，将通过探索雌激素在老年骨骼效应的分子机制，特别是雌激素的抗氧化特性、细胞质激酶介导的雌激素作用、活性氧以及老年骨细胞的出生和死亡之间的引人注目的联系，来研究雌激素损失对年龄相关的骨量和强度损失的贡献。项目2将研究氧化脂质（以及负责生成它们的酶，如Alox15，或介导其作用的转录因子，如pparty）对老年发生的成骨细胞生成减少和脂肪生成增加的贡献；每天注射甲状旁腺激素是治疗老年性骨质疏松症的合理方法，因为它们可以改善活性氧和氧化脂质对成骨细胞凋亡的不利影响。项目3将寻求一个机制解释，为什么年龄是比骨矿物质密度更重要的骨折风险因素。具体来说，我们将研究年龄相关的糖皮质激素分泌增加对骨细胞/腔隙系统完整性、流体流动、材料特性和受损骨积累的影响；以及这些因素对骨强度和骨密度不匹配的影响。最后，项目4将探索衰老过程中机械力的减少（来自体力活动的减少）增加骨细胞凋亡的可能性，从而导致骨质量恶化和异常修复过程，这两者都有助于骨强度下降。这项工作应该有助于我们更好地理解为什么老年人比年轻人更容易患骨质疏松症；或许还能确定针对这部分人群的最佳抗骨质疏松疗法。

DESCRIPTION (provided by applicant): The objective of this renewal application is three-fold. First, we plan to capitalize on our accomplishments in the last 10 years and provide a comprehensive dissection of the contribution of age-related changes in other organs or tissues (e.g., ovaries, bone marrow, adrenals), and the cellular and molecular mechanisms behind them, to the age-related loss of bone mass and strength versus the contribution of skeletal aging per se. Second, we will establish the impact of aging on various qualitative aspects of bone strength, including microarchitecture, prevalence of fatigue damage, bone turnover, and osteocyte number. Third, we will investigate the relative efficacy and mechanistic appropriateness of different therapeutic modalities on the aging skeleton in the context of the specific pathogenetic factors that contribute to age-associated osteoporosis. To achieve the goal of the Program, four Projects (supported by three Cores) will address, in a thematic and systematic manner, closely interrelated hypotheses, which will be tested using a variety of molecular and cell biology approaches, as well as normally aging C57BL/6 mice, and several other transgenic and knockout mice. In Project 1, the contribution of estrogen loss to the age-related loss of bone mass and strength will be investigated by exploring the molecular mechanisms of the skeletal effects of estrogens in old age, and in particular, the compelling link among the antioxidant properties of estrogens, cytoplasmic kinase-mediated estrogen actions, reactive oxygen species, and the birth and death of bone cells with old age. Project 2 will examine the contribution of oxidized lipids (and the enzymes responsible for their generation, e.g., Alox15, or the transcription factors that mediate their actions, e.g., PPARy), to the decreased osteoblastogenesis and increased adipogenesis that occurs with old age; and the exciting possibility that daily injections of PTH are rational therapy for age-related osteoporosis because they ameliorate the adverse effects of reactive oxygen species and oxidized lipids on osteoblast apoptosis. Project 3 will seek a mechanistic explanation for why age is a far more critical risk factor for fractures than bone mineral density. Specifically, we will study the impact of the age-related increase in glucocorticoid production on the integrity of the osteocyte/lacunarcanalicular system, fluid flow, material properties and the accumulation of damaged bone; and the contribution of these factors on the mismatch between bone strength and BMD. Finally, Project 4 will explore the possibility that reduced mechanical forces during aging (from reduced physical activity) increase osteocyte apoptosis and this leads to deterioration of bone quality and an aberrant repair process, both of which contribute to decreased bone strength. This work should help us better understand why elderly people suffer from osteoporosis a lot more than young people; and perhaps identify the optimal anti-osteoporosis therapy for this particular segment of the population.