Estrogen Receptor Signaling Pathways in Bone

骨中雌激素受体信号通路

• 批准号: 9249450
• 负责人: David G Monroe
• 金额: $ 39.33万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9249450
• 关键词: Address; Adrenergic Receptor; Adult; Affect; Age-Related Bone Loss; Apoptosis; Apoptotic; Attenuated; Biological Models; Bone Marrow; Bone Resorption; Bone structure; Cell Lineage; Cells; Clinical; Clinical Research; Complement; Conceptions; Data; Development; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Estrogen Replacements; Estrogens; Extracellular Signal Regulated Kinases; Financial compensation; Gene Expression; Gene Targeting; Human; In Vitro; Knockout Mice; Knowledge; Lead; Mediating; Mediator of activation protein; Modeling; Mus; Neuraxis; Osteoblasts; Osteoclasts; Osteocytes; Osteoporosis; Ovariectomy; Physiological; Physiology; Population; Population Study; Postmenopause; Premenopause; Prevention; Program Research Project Grants; Regulation; Role; Signal Pathway; Signal Transduction; Skeletal Development; Skeleton; Sympathetic Nervous System; System; Testing; Time; Uterus; Weight; Woman; aging population; beta-adrenergic receptor; bone; bone loss; bone mass; bone metabolism; cell type; defined contribution; in vivo; insight; mature animal; mouse model; novel; novel strategies; prevent; receptor; skeletal; tool

Project Summary Project 3 investigates the central theme of this program project grant (PPG), sympathetic nervous system (SNS) control of bone metabolism, by using a novel mouse model in Aim 1 to define the contribution of increased �-adrenergic receptor (�-AR) signaling to bone loss following estrogen (E) deficiency. Using microneurography, we found (see Project 1) that postmenopausal women have markedly increased sympathetic outflow as compared to premenopausal women. Moreover, in Project 3, we demonstrate that E treatment in vitro or E replacement in postmenopausal women markedly reduces �2-AR expression in osteoblastic cells, suggesting that E may modulate �-AR signaling in bone. Combined with previous studies indicating that, in mice, �2-ARs are the principal mediators of SNS effects on bone, these findings lead to our hypothesis in Aim 1 that E deficiency results in enhanced SNS signaling in bone and that �2-AR deletion in osteoblast lineage cells in adult mice at the time of ovariectomy (ovx) will prevent, or at least attenuate, ovx- induced bone loss. In Aims 2 and 3, Project 3 will better define E effects on bone metabolism beyond the interactions with SNS signaling being studied in Aim 1. For this, we will build on discoveries made previously in this PPG and will use novel mouse models that we have developed and validated. Thus, while skeleton is one of the main targets of E action, there are major gaps in our fundamental knowledge regarding E action on bone. First, all murine models of estrogen receptor (ER) action in mice have utilized deletions from conception onward, making it impossible to distinguish the effects of E on skeletal development from those on regulation of the adult skeleton or on age-related bone loss. We have developed and extensively validated a Cre- inducible system for deletion of ERs in the adult mouse. Our preliminary data using this system demonstrates that loss of ER� in adult mice has no effect on bone mass, whereas the uterus appears similar to an ovx d mouse. This suggests that in the complete absence of ER�, ER� may be compensating for the loss of ER� in bone. We will test this hypothesis in Aim 2, where we will determine if, in the absence of ER�, ER� compensates for loss of ER� in bone in adult mice. A second, major unresolved question is which cell type is most crucial for triggering bone loss when E is withdrawn in the adult mouse (or human)? This is a very different question from that addressed by current mouse knock out (KO) models which utilize osteoblast-, osteoclast-, or osteocyte-specific ER� deletion from conception onwards. Thus, while ER� deletion during skeletal development in each of these cell types affects bone mass and structure, none of these models address the issue of which cell type is most important for triggering bone loss following E deficiency in the adult animal. In Aim 3 we will test the hypothesis that this crucial cell is the osteocyte, and that deletion of both ER� and ER� in the osteocyte will be necessary to trigger bone loss in the adult mouse and to mimic the effects of ovx.

项目摘要 项目3研究该计划项目资助（PPG）的中心主题，交感神经系统 (SNS)控制骨代谢，通过使用目的1中的新型小鼠模型来确定 雌激素（E）缺乏后，β-肾上腺素能受体（β-AR）信号增加导致骨丢失。使用 显微神经造影，我们发现（见项目1），绝经后妇女有显着增加， 与绝经前妇女相比，交感神经流出。此外，在项目3中，我们证明了E 体外治疗或绝经后妇女E替代治疗显著降低了β 2-AR表达， 成骨细胞，表明E可能调节骨中β-AR信号。结合以往的研究 这表明，在小鼠中，β 2-AR是SNS对骨作用的主要介质，这些发现导致我们的研究结果。 目标1中的假设，即E缺乏导致骨中SNS信号增强，而β 2-AR缺失导致骨中β 2-AR信号增强。 在卵巢切除术（OVX）时，成年小鼠中的成骨细胞谱系细胞将防止或至少减弱OVX。 导致骨质流失。在目标2和3中，项目3将更好地定义E对骨代谢的影响， 目标1中正在研究与SNS信号的相互作用。为此，我们将建立在以前的发现， 这个PPG将使用我们开发和验证的新型小鼠模型。因此，虽然骨架是一个 在E行动的主要目标中，我们对E行动的基本知识存在重大差距， 骨头首先，所有雌激素受体（ER）作用的小鼠模型都利用了从受孕开始的缺失 因此，不可能区分E对骨骼发育的影响和对调节的影响 或与年龄相关的骨质流失。我们已经开发并广泛验证了Cre- 用于在成年小鼠中缺失ER的诱导系统。我们使用该系统的初步数据表明， 在成年小鼠中，ER β的丢失对骨质没有影响，而子宫似乎类似于ovx d。 老鼠.这表明，在完全缺乏ER β的情况下，ER β可能会补偿ER β的损失。 骨头我们将在目标2中检验这一假设，在目标2中，我们将确定，在没有ER β的情况下，ER β 补偿成年小鼠骨中ER β的损失。第二个尚未解决的主要问题是， 在成年小鼠（或人类）中，当E被撤回时，对触发骨质流失最关键的是什么？这是一个非常 与目前利用成骨细胞的小鼠敲除（KO）模型所解决的问题不同， 破骨细胞或骨细胞特异性ER β从受孕开始缺失。因此，当ER缺失时， 这些细胞类型中的每一种的骨骼发育都会影响骨量和结构，但这些模型中没有一种 解决的问题，哪种细胞类型是最重要的触发骨丢失后，在成人缺乏E 动物在目的3中，我们将检验这一假设，即这一关键细胞是骨细胞，而ER和ER β基因的缺失， 骨细胞中的ER β和ER β是引发成年小鼠骨丢失所必需的， ovx。