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

描述（由申请人提供）：骨质疏松症是一种主要的健康问题，与年龄相关的循环性类固醇减少有关，主要影响骨骼松质区骨量和结构。激素疗法和运动可以有效地抵消这种骨质流失。这些治疗因子可能起作用的途径之一是雌激素受体α (er - α)。然而，雌激素、er - α和机械负荷维持松质骨量或刺激骨生长的机制尚不清楚。本研究拟评估的假设是：(1)小鼠胫骨干骺端对负荷的结构和物质反应在青春期周围的小鼠中最大，并随着年龄的增长而降低，这反映了er - α在骨中的表达；(2)由于er - α被认为是骨骼中负荷适应性反应的主要影响因素，在每个相应年龄，er - α敲除小鼠的这种反应将相对于野生型显著减弱。具体目的：确定野生型和er - α敲除小鼠胫骨近端干骺端皮质松质对年龄负荷的反应。这些目标将通过使用外部加载装置对三个年龄组的雌性野生型和er - α敲除小鼠的胫骨施加压缩载荷来实现。通过检查皮质松质结构、材料特性、细胞活性和干骺端相对于未负重肢体的承载能力，我们将探讨与年龄和er - α表达相关的骨对负重方案的反应。意义：本项目将提供关于er - α在正常骨发育和负荷机械转导中的作用的独特数据。这项工作将证明体内负荷维持或刺激随年龄增长的松质骨生长的功效，以及er - α在正常骨发育和介导骨对外部负荷的反应中的作用。本研究的目的是了解在雌激素存在和不存在的情况下，松质骨适应负荷的分子和力学机制。通过提出的研究获得的见解对于制定抑制年龄相关和绝经后骨质流失的治疗策略至关重要。

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.