Heparan Sulfate in Skeletal Development and Diseases

描述（由申请人提供）：硫酸乙酰肝素（HS）结合并功能调节多种生长因子和形态因子。遗传学研究表明，HS是模型动物许多发育信号通路的重要组成部分。然而，我们对HS在哺乳动物骨骼发育和重塑中的作用的了解仍然非常有限，这是在HS异常表达影响最大的组织是骨骼的情况下。例如，编码HS合成所必需的酶的基因突变导致遗传性多发性外生骨病（HME），这是临床骨科中最常见的遗传性骨疾病之一。在成人中，长期肝素治疗血栓栓塞和其他血管疾病的患者经常导致类似骨质疏松症的低骨量状况。提高对HS在发育和成人骨骼系统中调节生长因子信号传导机制的理解对于设计治疗这些疾病的方法至关重要。为了实现这一长期目标，我们采用条件小鼠遗传学方法来解剖HS在骨骼发育和生理中的功能。我们的证据表明，HS对正常的骨骼模式和骨骼细胞分化至关重要，参与了关键的生长因子信号通路。基于这些和其他初步数据，我们提出以下具体目标：探讨软骨形成中HS功能的时间依赖性和结构特异性。2. 确定软骨形成过程中HS调控BMP功能的机制。3. 确定HS在发育性骨形成和骨量调节中的作用。所提出的研究将对HME的发病机制产生新的见解，并可能有助于确定骨质疏松症的新药物靶点。公共卫生相关性：硫酸肝素对正常的骨骼发育和生理至关重要，遗传学（遗传性多发性外生性增生）和代谢性（肝素诱导的骨质疏松症）骨病的存在与硫酸肝素的异常表达直接相关。本项目将采用先进的小鼠遗传学来阐明硫酸肝素调节骨细胞功能的分子机制。这些研究将对遗传性多发性外生性增生的发病机制产生新的见解，并可能有助于确定骨质疏松症的新药物靶点。

DESCRIPTION (provided by applicant): Heparan sulfate (HS) binds and functionally modulates a number of growth factors and morphogens. Genetic studies have revealed that HS is an integral component of many developmental signaling pathways in model animals. However, our understanding of the role of HS in the mammalian skeletal development and remodeling is still quite limited, and this is in spite of the fact that the tissue most affected by aberrant expression of HS is bone. For example, mutations of the gene encoding an enzyme essential for HS synthesis cause Hereditary Multiple Exostosis (HME), which is one of the most common genetic bone disorders in clinical orthopedics. In the adults, long-term heparin treatment for patients with thromboembolism and other vascular diseases often leads to a low bone mass condition resembling osteoporosis. The improved understanding of the mechanisms by which HS regulates growth factor signaling in the developing and adult skeletal system is critical for devising therapies for these diseases. Toward this long- term goal, we have employed conditional mouse genetics approaches to dissect the function of HS in skeletal development and physiology. Our evidence suggests that HS is essential for normal skeletal patterning and skeletal cell differentiation, being involved in key growth factor signaling pathways. Based on these and other preliminary data, we propose the following specific aims: 1. To dissect time-dependence and structural specificity of HS function in chondrogenesis. 2. To determine the mechanisms by which HS regulates BMP function during chondrogenesis. 3. To determine the role of HS in developmental bone formation and the regulation of bone mass. The proposed studies will generate new insights into the pathogenesis of HME, and may help define new drug targets for osteoporosis. PUBLIC HEALTH RELEVANCE: Heparan sulfate is essential for normal bone development and physiology, as illustrated by the existence of the genetic (hereditary multiple exostosis) and metabolic (heparin- induced osteoporosis) bone diseases that are directly linked to aberrant expression of heparan sulfate. This project will employ advanced mouse genetics to elucidate the molecular mechanisms by which heparan sulfate regulates bone cell function. The proposed studies will generate new insights into the pathogenesis of hereditary multiple exostosis, and may help define new drug targets for osteoporosis.