Response of the tibia to loading in wild-type and estrogen receptor knockout mice

野生型和雌激素受体敲除小鼠胫骨对负荷的反应

• 批准号: 7576874
• 负责人: RUSSELL P MAIN
• 金额: $ 5.01万
• 依托单位: CORNELL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-12 至 2010-04-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7576874
• 关键词: Address; Adult; Affect; Age; Animals; Architecture; Bone Development; Bone Growth; Data; Devices; Elements; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Exercise; Female; Fourier Transform; Fracture; Goals; Gonadal Steroid Hormones; Growth; Growth and Development function; Health; Immunohistochemistry; Knock-out; Knockout Mice; Limb structure; Link; Maintenance; Measures; Mechanics; Mediating; Metaphysis; Methods; Modeling; Molecular; Mus; Osteoporosis; Pathway interactions; Physiological; Play; Postmenopausal Osteoporosis; Property; Protocols documentation; Relative (related person); Research; Role; Skeleton; Testing; Therapeutic; Treatment Protocols; Weight-Bearing state; Wild Type Mouse; Work; age group; age related; bone; bone loss; bone mass; hormone deficiency; hormone therapy; human ESR1 protein; in vivo; infrared microscopy; insight; receptor; research study; response; skeletal; tibia; tomography

DESCRIPTION (provided by applicant): Osteoporosis is a major health concern linked to age-related decreases in circulating sex steroids that primarily affects bone mass and architecture in cancellous regions of the skeleton. Hormone therapy and exercise can be effective in counteracting this bone loss. One pathway by which these therapeutic factors may act is estrogen receptor-alpha (ER-alpha). However, the mechanisms by which estrogen, ER-alpha and mechanical loading maintain cancellous bone mass or stimulate bone growth are not well understood. The hypotheses to be evaluated in the proposed research are that (1) the structural and material response of the mouse tibial metaphysis to load will be greatest in peripubescent mice and will decrease with age to adulthood, mirroring ER-alpha expression in the bone; and (2) as ER-alpha is expected to be the primary effector of the adaptive response to load in the skeleton, this response will be significantly diminished in ER-alpha knockout mice relative to the wild types at each corresponding age. Specific Aims: To determine the corticocancellous response of the proximal metaphysis of the mouse tibia to loading with age in both wild type and ER-alpha knockout mice. These aims will be accomplished by applying compressive loads to the tibiae of three age groups of female wild type and ER-alpha knockout mice using an external loading device. The bone's response to the loading regimen in relation to age and ER-alpha expression will be addressed by examining the corticocancellous architecture, material properties, cellular activities, and load bearing capacity in the metaphysis relative to the unloaded limb. Significance: This project will produce unique data regarding the role of ER-alpha in normal bone development and load mechanotransduction. This work will demonstrate the efficacy of in vivo loading to maintain or stimulate growth in cancellous bone with age and the role of ER-alpha in normal bone development and in mediating bone's response to external loads. The goal of the proposed study is to understanding the molecular and mechanical mechanisms by which cancellous bone adapts to load, both in the presence and absence of estrogen. The insights gained by the proposed study are critical for developing therapeutic strategies to inhibit age-related and postmenopausal bone loss.

描述（由申请人提供）：骨质疏松症是与年龄相关的性类固醇相关的主要健康问题，主要影响骨骼取消区域的骨骼质量和建筑。激素疗法和运动可以有效抵消这种骨质流失。这些治疗因素可以起作用的一种途径是雌激素受体-Alpha（ER-Alpha）。然而，雌激素，α和机械负荷维持取消骨骼或刺激骨骼生长的机制尚不清楚。在拟议的研究中要评估的假设是（1）小鼠胫骨胫骨对负载的结构和物质反应在外叶小鼠中将是最大的，并且随着年龄的成年年龄的减少，反映了骨骼中的ER-Alpha表达； （2）由于ER-Alpha预计将是骨骼载荷反应的主要效应器，因此相对于每个相应年龄段的野生类型，ER-Alpha敲除小鼠中的反应将显着减少。具体目的：确定小鼠胫骨近端冲突对野生型和ER-Alpha敲除小鼠的近端冲突的皮质角质反应。这些目标将通过使用外部加载装置的三个年龄段的女性野生型和ER-Al-Alpha敲除小鼠的胫骨来实现。骨骼对年龄和ER-α表达的负载方案的反应将通过检查与卸载的肢体相对于载液的皮层结构，材料特性，细胞活性，细胞活性和负载能力来解决。意义：该项目将产生有关ER-Alpha在正常骨骼发育和负载机械转导的作用的独特数据。这项工作将证明体内负荷随着年龄的增长以及ER-α在正常骨发育中的作用以及介导骨骼对外部载荷的反应时，体内负荷的有效性。拟议的研究的目的是理解在存在和不存在雌激素的情况下，可以通过这种机制适应了骨的负载。拟议的研究获得的见解对于制定治疗策略以抑制年龄相关和绝经后骨质流失至关重要。