IN VIVO SKELETAL RESPONSE TO MECHANICAL STIMULATION

体内骨骼对机械刺激的反应

基本信息

批准号：
2683150
负责人：
DIANE M CULLEN
金额：
$ 9.59万
依托单位：
CREIGHTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-04-01 至 2000-03-31
项目状态：
已结题

项目摘要

DESCRIPTION: (Adapted from the Investigator's Abstract) The fundamental goal of this research is to understand the interplay of aging, mechanical regulation of bone mass, and osteoporosis. In osteoporosis, fractures occur because of structural failure during normal mechanical loading, largely due to reduced skeletal mass. This application proposes to study the skeletal biology of mechanical loading because mechanical loading is a powerful regulator of bone mass in vivo. In addition to hormonal, nutritional, and genetic factors, the reduced bone mass in osteoporosis can be related to reduced mechanical loading from decreased physical activity, or to an age- related reduction of the biological response to normal mechanical loading, or a combination. In any case, understanding the mechanism(s) involved in the biological response to mechanical loading will increase the ability to devise lasting cures or preventions for osteoporosis. This project will investigate the biological response to mechanical loading of the skeleton by using an in vivo model of controlled external loading to study age, estrogen deficiency, a common agent for osteoporosis treatment, and autocrine/paracrine mediators as transducers of the loading signal. The hypotheses to be tested are: (1) the age-related decrease in bone response to mechanical stimulation is progressive, (2) bone adaptation to mechanical loads is similar in pattern, but lower in magnitude in estrogen deficient rats than in control rats, (3) bisphosphonates depress the bone response to mechanical loading, (4) prostaglandins mediate the transduction of mechanical signals to bone cell responses, and (5) changes in periosteal mRNA expression after mechanical stimulation are depressed with age. The specific aims are: (1) to compare the bone forming response to similar mechanical loads in four age groups of rats (Fischer 344), (2) to compare the bone forming response in estrogen deplete and control rats at four ages, (3) to test the effect of bisphosphonates, a treatment to prevent estrogen-related bone loss, on the bone forming response to mechanical loading, (4) to test the effect of indomethacin, a prostaglandin inhibitor, on the bone formation response to moderate and high bending forces, and (5) to compare mRNA expression after mechanical loading in four age groups of rats. The methods of assessment include histomorphometry, biomechanics, and mRNA analysis. The results of these studies will lead to an understanding of the aged bone response to mechanical loading and the cascade of signals from mechanical loading to increased bone cell activity. This knowledge will help devise methods of increasing the skeletal response to daily mechanical loading and perhaps maintain bone mass with aging.

描述：（改编自研究者摘要）基本原理这项研究的目标是了解衰老的相互作用，骨量的机械调节和骨质疏松症。在骨质疏松症中，正常机械过程中由于结构失效而发生断裂负荷，主要是由于骨骼质量减少。这个应用程序提议研究机械载荷的骨骼生物学，因为机械负荷是体内骨量的强大调节剂。在除了荷尔蒙、营养和遗传因素外，骨质减少骨质疏松症的质量可能与机械负荷的减少有关身体活动减少，或与年龄相关的身体活动减少对正常机械负荷或其组合的生物反应。在无论如何，了解生物相关的机制对机械负载的响应将提高设计能力持久治疗或预防骨质疏松症。该项目将研究机械负荷的生物反应通过使用受控外部负载的体内模型来构建骨骼研究年龄、雌激素缺乏、骨质疏松症的常见因素治疗和自分泌/旁分泌介质作为传感器加载信号。待检验的假设是：（1）与年龄相关的骨量减少对机械刺激的反应是渐进的，（2）骨骼适应与机械载荷的模式相似，但幅度较低雌激素缺乏的大鼠与对照大鼠相比，（3）双膦酸盐抑制骨骼对机械负荷的反应，（4）前列腺素介导机械信号向骨细胞反应的转导， (5)机械治疗后骨膜mRNA表达的变化刺激随着年龄的增长而减弱。具体目标是：（1）比较四种材料中类似机械负载的骨形成反应各年龄组大鼠（Fischer 344），（2）比较骨形成四个年龄段雌激素消耗大鼠和对照大鼠的反应，(3) 进行测试双膦酸盐的作用，一种预防雌激素相关的治疗方法骨质流失，对机械负荷的骨形成反应，(4) 测试前列腺素抑制剂吲哚美辛对骨骼的影响地层对中度和高弯曲力的响应，以及（5）比较机械负荷后四个年龄组的 mRNA 表达老鼠。评估方法包括组织形态计量学、生物力学、和 mRNA 分析。这些研究的结果将导致了解老化骨骼对机械负荷的反应以及从机械负荷到骨细胞增加的级联信号活动。这些知识将有助于设计增加骨骼对日常机械负荷的反应并可能维持骨骼质量随着老化。