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

描述(申请人提供)：骨质疏松症是一个主要的健康问题，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域的骨量和结构。激素治疗和运动可以有效地抵消这种骨丢失。这些治疗因子发挥作用的一个途径是雌激素受体-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。拟议的研究中将要评估的假设是：(1)青春期小鼠胫骨干骺端对负荷的结构和材料反应将最大，并随着年龄的增长而降低，这反映了ER-α在骨骼中的表达；(2)由于ER-α被认为是骨骼对负荷的适应性反应的主要效应者，因此ER-α基因敲除小鼠的这种反应在各个相应年龄段相对于野生型将显著减弱。具体目的：在野生型和ER-α基因敲除小鼠中，确定小鼠胫骨近端干骺端的皮质松质细胞对负荷随年龄增长的反应。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基因敲除小鼠的胫骨施加压缩载荷来实现。骨骼对负荷方案的反应与年龄和ER-α的表达有关，将通过检测相对于未负荷肢体的干骺端的皮质松质细胞结构、材料特性、细胞活动和承载能力来解决。意义：该项目将产生关于ER-α在正常骨骼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松质骨随年龄增长的有效性，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。这项拟议研究的目的是了解松质骨在雌激素存在和不存在的情况下适应负荷的分子和力学机制。通过拟议的研究获得的见解对于开发治疗策略以抑制与年龄相关的和绝经后的骨丢失至关重要。

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.