Molecular & cellular Mechanisms of Osteoporosis

描述（由申请人提供）：本续期申请的目的是三重。首先，我们计划利用我们在过去10年中取得的成就，全面剖析其他器官或组织中与年龄相关的变化（例如，卵巢、骨髓、肾上腺），以及它们背后的细胞和分子机制，与年龄相关的骨量和强度损失相对于骨骼衰老本身的贡献。其次，我们将建立老化对骨强度的各个定性方面的影响，包括微结构，疲劳损伤的患病率，骨转换和骨细胞数量。第三，我们将调查的相对疗效和机械适当性的不同治疗方式对老化骨骼的特定致病因素，有助于年龄相关性骨质疏松症的背景下。为了实现该计划的目标，四个项目（由三个核心支持）将以主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老化的C57 BL/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，将通过探索雌激素对老年人骨骼影响的分子机制，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、活性氧和骨细胞的出生和死亡之间的联系，研究雌激素损失对与年龄相关的骨量和强度损失的贡献。项目2将研究氧化脂质的贡献（以及负责其生成的酶，例如，Alox 15或介导其作用的转录因子，例如，PPARy），降低成骨细胞生成和增加脂肪生成，这与老年有关;以及令人兴奋的可能性，即每天注射PTH是年龄相关性骨质疏松症的合理治疗，因为它们改善了活性氧和氧化脂质对成骨细胞凋亡的不利影响。项目3将寻求一个机械解释，为什么年龄是一个比骨密度更重要的骨折风险因素。具体而言，我们将研究与年龄相关的糖皮质激素产生增加对骨细胞/骨腔隙系统的完整性、流体流动、材料特性和受损骨的积累的影响;以及这些因素对骨强度和BMD之间不匹配的贡献。最后，项目4将探讨衰老过程中机械力减少（由于体力活动减少）增加骨细胞凋亡的可能性，这会导致骨质量恶化和异常修复过程，这两者都有助于降低骨强度。这项工作应该帮助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;也许还能为这一特定人群确定最佳的抗骨质疏松症治疗方法。

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.