Heparan Sulfate in Skeletal Development and Diseases

说明(申请人提供)：硫酸乙酰肝素(HS)结合并在功能上调节一些生长因子和形态因子。遗传学研究表明，在动物模型中，HS是许多发育信号通路的组成部分。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相当有限，尽管受HS异常表达影响最大的组织是骨。例如，编码HS合成所必需的酶的基因突变会导致遗传性多发性外生骨瘤(HME)，这是临床骨科最常见的遗传性骨病之一。在成人中，长期使用肝素治疗血栓栓塞症和其他血管疾病的患者通常会导致类似骨质疏松的低骨量状况。更好地了解HS调节发育和成人骨骼系统中生长因子信号的机制对于设计这些疾病的治疗方法至关重要。为了实现这一长期目标，我们采用了条件小鼠遗传学的方法来剖析HS在骨骼发育和生理学中的功能。我们的证据表明，HS对正常的骨骼构型和骨骼细胞分化是必不可少的，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，我们提出了以下具体目标：1.剖析HS功能在软骨形成中的时间依赖性和结构特异性。2.探讨HS在软骨形成过程中对BMP功能的调控机制。3.确定HS在发育性骨形成和骨量调节中的作用。拟议的研究将对HME的发病机制产生新的见解，并可能有助于确定治疗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，遗传性(遗传性多发性骨软骨瘤)和代谢性(肝素诱导的骨质疏松症)骨病的存在就证明了这一点，这些疾病与硫酸肝素的异常表达直接相关。该项目将利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。拟议的研究将对遗传性多发性骨软骨瘤的发病机制产生新的见解，并可能有助于确定治疗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.