AUGMENTATION OF TRABECULAR BONE BY LOW MAGNITUDE STRAIN

描述（由申请人提供）：短时间（<=20min.d -1）极低强度（<<10微应变），高频（15- 90hz）机械刺激（LMMS）非侵入性地引入骨骼，增加小梁骨的数量和质量。经过一年的负荷，成年羊股骨髁的骨小梁体积分数增加10.5%，纵向刚度增加12%，强度增加27%。早期对人类的研究表明，这种生物力学模式可能作为预防甚至逆转骨质疏松症的干预手段。尽管LMMS在治疗这种致残性疾病方面可能有希望，但这些信号有效的生物学和物理机制尚未得到解决。为了更好地理解这些低水平信号的合成代谢机制，将采用三个具体目标：为了开始识别那些参与合成代谢反应的基因，对LMMS （C57BL/6J）有反应的成年雌性小鼠将每天接受LMMS治疗（10分钟，45 Hz, 0.3g）。早期到晚期（1,4,10和21 d） 15个候选基因的表达模式，代表那些参与骨的形成和吸收，将被量化，并与骨重塑和形态学的改变，以及基线和长期对照动物进行比较。2. 为了帮助验证这些基因在调节骨适应中的作用，将对LMMS （C3H/HeJ）无反应的成年雌性小鼠暴露于信号和基因活性的改变中（如上所述）。3. 为了开始解决LMMS在一些组织中合成代谢的物理机制，但不是所有组织，我们将测试一个假设，即反应小鼠品系中的骨细胞以一种不同于无反应品系的骨细胞的方式改变其自身形态和与腔隙的相互作用。这些研究将有助于确定细胞如何感知和响应其物理环境中的细微变化，并代表了建立骨质疏松症非药物、非侵入性治疗的机制基础的关键一步。

DESCRIPTION (provided by applicant): Short periods (<=20min.d -1) of extremely low magnitude (<<10 microstrain), high frequency (15-90 Hz) mechanical stimuli (LMMS) introduced non-invasively into the skeleton augment both the quantity and quality of trabecular bone. Following one year of loading, femoral condyles from adult sheep realize a 10.5% increase in trabecular volume fraction, a 12% increase in longitudinal stiffness and a 27% increase in strength. Early work on humans shows potential that this biomechanical modality may serve as an intervention to prevent, and even reverse osteoporosis. As promising as LMMS may be in treating this crippling disease, the biological and physical mechanisms whereby these signals are effective has not been addressed. Three specific aims will be used to better understand the mechanisms by which these low-level signals are anabolic: 1. To begin identifying those genes involved in the anabolic response, adult female mice responsive to LMMS (C57BL/6J) will be subject to daily LMMS treatment (10 min, 45 Hz, 0.3g). Early through late (1, 4, 10 & 21 d) patterns of expression of fifteen candidate genes, representing those involved in formation and resorption of bone, will be quantified and compared to alterations in bone remodeling and morphology, as well as to baseline and long-term control animals. 2. To help validate the role of these genes in regulating bone adaptation, adult female mice that are unresponsive to LMMS (C3H/HeJ) will be exposed to the signal and alterations in gene activity examined (as above). 3. To begin to address a physical mechanism whereby LMMS is anabolic in some, but not all, tissues, we will test the hypothesis that the osteocyte in the responsive mouse strain alters its own morphology and interaction with the lacunae in a manner distinct from osteocytes in the unresponsive strain. These studies will help define how the cell perceives and responds to subtle changes in its physical environment, and represents a critical step in establishing the mechanistic basis for a non-pharmacologic, non-invasive treatment for osteoporosis.