Effects of High Glucose on Bone Cell Mechanosensing, Transduction, and Signaling

描述(申请人提供)：胰岛素依赖型糖尿病(IDDM；1型糖尿病)患者表现出更高的骨丢失和骨质疏松症和相关骨折的风险增加。然而，导致IDDM骨丢失的机制仍不完全清楚。众所周知，骨量是通过骨重建来维持的，骨重建是一个涉及成骨细胞和骨细胞形成新骨和破骨细胞吸收现有骨的过程。骨重建是通过体力活动持续施加于骨骼的机械刺激来调节的，因此，骨细胞/成骨细胞对机械负荷的适当反应对于维持骨功能和骨骼完整性至关重要。这个R01应用的主要目的是检验这一新的假设，即骨机械感觉和转导系统组件的表达改变是导致IDDM骨细胞功能障碍和更高的骨丢失的主要机制。为此，我们将对骨细胞系进行全面的体外研究，这将独特地与在体骨生理学和对1型糖尿病秋田鼠模型的在位骨组织分析相结合。拟议的体外研究将为高糖对骨细胞检测和对机械刺激的反应的影响提供机械方面的见解。对年龄匹配的对照和使用或不使用胰岛素的秋田小鼠进行的体内和最终的原位研究将确定糖尿病和相关的高血糖对机械负荷下骨形成的影响，并评估骨机械信号的改变在糖尿病更高的骨丢失中的作用。这些研究将由一位具有生物医学工程背景的新研究员指导，他已经开始在整形外科系首次任命教员。研究将结合生物医学工程、药理学、生理学和分子生物学领域的初级和高级研究人员的广泛专业知识，以及最先进的生化、活细胞成像、组织形态计量学研究和非侵入性活体整体动物骨骼成像。这项拟议的研究不仅有望促进对糖尿病骨量减少的机制的了解，突出高糖对骨机械感觉/转导系统的有害影响，而且还将使人们认识到早期严格控制血糖对预防和逆转糖尿病骨丢失的重要性。

DESCRIPTION (provided by applicant): Patients with insulin dependent diabetes mellitus (IDDM; Type 1 diabetes) display higher bone loss and increased risk for osteoporosis and related bone fractures. However, the mechanisms that underlie bone loss in IDDM are still not fully understood. It is well established that bone mass is maintained by bone remodeling, a process that involves formation of new bone by osteoblasts and osteocytes and resorption of existing bone by osteoclasts. Bone remodeling is regulated by mechanical stimuli imposed continuously to the skeleton by physical activity, and proper response of osteocytes/osteoblasts to mechanical loading is thus essential for maintenance of bone function and skeletal integrity. The main goal of this R01 application is to test the novel hypothesis that altered expression of components of bone mechanosensory and transduction systems is a central mechanism leading to bone cell dysfunction and higher bone loss in IDDM. For this we will use comprehensive in vitro studies with bone cell lines that will be uniquely combined with in vivo bone physiology and in situ bone tissue analysis on the Type 1 diabetic Akita mouse model. The proposed in vitro studies will provide mechanistic insights into effects of high glucose on bone cell detection and response to mechanical stimuli. The in vivo and ultimate in situ studies with control age- matched and Akita mice treated with or without insulin will determine the impact of diabetes and associated high glucose on bone formation in response to mechanical loading, and evaluate the contribution of altered bone mechanosignaling to the higher bone loss in diabetes. These studies will be directed by a new investigator who has a background in biomedical engineering and has begun a first faculty appointment in a Department of Orthopaedic Surgery. Studies will combine the broad expertise of junior and senior researchers in the areas of biomedical engineering, pharmacology, physiology and molecular biology, and state-of-the-art biochemical, live cell imaging, histomorphometric studies and non-invasive in vivo whole animal bone imaging. The proposed studies are not only expected to advance understanding of mechanisms underlying diabetic osteopenia, highlighting the deleterious effects of high glucose on bone mechanosensory/transduction systems, but will also bring awareness to the importance of an early and tight glycemic control to prevent and reverse bone loss in diabetes.