AUGMENTATION OF TRABECULAR BONE BY LOW MAGNITUDE STRAIN

通过低强度应变增强骨小梁

• 批准号: 6950036
• 负责人: CLINTON T RUBIN
• 金额: $ 26.49万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-12-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6950036
• 关键词: biological signal transduction; bone development; bone metabolism; cell adhesion; cell cell interaction; cell morphology; cytoskeleton; developmental genetics; electron microscopy; electrostimulus; femur; gene expression; genetic transcription; genetically modified animals; histology; immunocytochemistry; laboratory mouse; mechanical stress; morphometry; osteocytes; osteoporosis; physiologic bone resorption; polymerase chain reaction; substantia spongiosa; tibia

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.

描述（由申请人提供）：短时间（<=20min.d -1）极低强度（<<10 微应变）、高频（15-90 Hz）机械刺激（LMMS）以非侵入性方式引入骨骼，可增强骨小梁的数量和质量。经过一年的加载，成年绵羊的股骨髁小梁体积分数增加了 10.5%，纵向刚度增加了 12%，强度增加了 27%。早期对人类的研究表明，这种生物力学方式可以作为预防甚至逆转骨质疏松症的干预措施。尽管 LMMS 在治疗这种严重疾病方面可能很有前景，但这些信号有效的生物和物理机制尚未得到解决。将使用三个具体目标来更好地理解这些低水平信号的合成代谢机制： 1. 为了开始识别参与合成代谢反应的基因，对 LMMS (C57BL/6J) 敏感的成年雌性小鼠将接受每日 LMMS 治疗（10 分钟，45 Hz，0.3g）。代表参与骨形成和吸收的十五个候选基因从早期到晚期（1、4、10和21天）的表达模式将被量化，并与骨重塑和形态的变化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，对 LMMS (C3H/HeJ) 无反应的成年雌性小鼠将暴露于所检查的信号和基因活性变化（如上所述）。 3. 为了开始解决 LMMS 在某些组织（但不是所有组织）中合成代谢的物理机制，我们将测试以下假设：响应小鼠品系中的骨细胞以与无响应品系中的骨细胞不同的方式改变其自身形态以及与腔隙的相互作用。这些研究将有助于确定细胞如何感知和响应其物理环境的微妙变化，并代表了为骨质疏松症的非药物、非侵入性治疗建立机制基础的关键一步。