AUGMENTATION OF TRABECULAR BONE BY LOW MAGNITUDE STRAIN

描述（由申请人提供）：短时间（<= 20分钟. d-1）的极低幅度（<<10微应变）、高频（15-90 Hz）机械刺激（LMMS）非侵入性地引入骨骼，增加骨小梁的数量和质量。经过一年的加载，成年绵羊股骨髁实现了10.5%的骨小梁体积分数增加，纵向刚度增加12%，强度增加27%。对人类的早期研究显示，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措施。尽管LMMS在治疗这种致残性疾病方面可能很有希望，但这些信号有效的生物和物理机制尚未得到解决。三个具体的目标将被用来更好地理解这些低水平信号是合成代谢的机制：1。为了开始鉴定参与合成代谢反应的那些基因，对LMMS（C57 BL/6 J）有反应的成年雌性小鼠将每天进行LMMS处理（10分钟，45 Hz，0.3 g）。将对15个候选基因（代表参与骨形成和再吸收的基因）的早期至晚期（1、4、10和21天）表达模式进行定量，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（C3 H/HeJ）无反应的成年雌性小鼠暴露于检测的信号和基因活性的改变（如上所述）。3.为了开始讨论LMMS在某些（但不是全部）组织中合成代谢的物理机制，我们将检验以下假设：反应性小鼠品系中的骨细胞以不同于无反应品系中的骨细胞的方式改变其自身形态和与骨陷窝的相互作用。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.