SERUM IGF-1 DELIVERY SYSTEM AND ITS ROLE IN DETERMINING SKELETAL INTEGRITY

血清 IGF-1 输送系统及其在确定骨骼完整性中的作用

• 批准号: 7659674
• 负责人: Shoshana Yakar
• 金额: $ 35.73万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7659674
• 关键词: Acids; Address; Adult; Affect; Animal Model; Animals; Binding; Biological Preservation; Biology; Blood Circulation; Bone Density; Bone remodeling; Cell physiology; Cells; Complex; Data; Disease; Dissection; Endocrine; Exhibits; Fracture; Gene Silencing; Genetic; Global Change; Growth; Half-Life; Hepatic; Human; Impairment; In Vitro; Individual; Insulin-Like Growth Factor I; Insulin-Like Growth-Factor-Binding Proteins; Knock-out; Knockout Mice; Lead; Length; Liver; Maintenance; Marrow; Modeling; Mus; Obesity; Osteoblasts; Osteoclasts; Osteoporosis; Outcome; Phenotype; Population; Protein Subunits; Recombinant IGF-I; Recombinants; Risk Factors; Role; Secondary to; Serum; Somatotropin; System; Testing; Tissues; autocrine; bone; bone cell; bone turnover; cohort; in vivo; insight; mouse model; mutant; osteoclastogenesis; paracrine; response; skeletal; skeletal tissue; substantia spongiosa; trait

DESCRIPTION (provided by applicant): Previous human studies have established a correlation between serum IGF-1 levels and bone mineral density (BMD) and defined serum IGF-1 as a risk factor for fracture. However, these studies have largely focused on BMD (a poor indicator of bone biology), have not explained how different bone traits (such as cortical and trabecular bone) correlate with serum IGF-1, nor how these traits are regulated by serum IGF-1. Animal studies of the GH/IGF axis were not able to distinguish between serum and local IGF-1 action, therefore very little data exists detailing the significance of serum IGF-1 and its complex formation in determining bone trait outcomes. Addressing those questions requires genetic dissection of the IGF-1 delivery components and therefore, the use of unique animal models that modulate delivery of IGF-1 rather than global changes or tissue specific changes in IGF-1 expression. We have recently generated two mouse models of serum IGF-1 deficiency which allow us to delineate the effects of serum IGF-1 levels and its delivery system on skeletal parameters in vivo; liver-specific IGF-1 deficient (LID) mice with 80% reduction in serum IGF-1 but normal IGF-1 expression in extra-hepatic/skeletal tissues, and the ALS knock out (ALSKO) mice, which exhibit 60% reduction in serum IGF-1 due to impaired ternary complex formation, thereby shortening IGF-1 half life. Despite the similar reductions in serum IGF-1 levels, LID and ALSKO mice have a very distinct skeletal phenotype. Both mutants show reduced BMD, however, LID mice preserve their trabecular bone, while ALSKO mice have a significant decrease in trabecular bone volume. Moreover, unlike the LIDs, ALSKO mice do not have an anabolic response to PTH, show impaired osteoclastogenesis and have increased marrow adiposity. Therefore, our hypothesis is that the IGF-1 delivery complex (with ALS), rather than circulating IGF-1 alone, determines skeletal acquisition and remodeling. We propose to 1. Determine the extent to which circulating IGF-1 impacts peak skeletal acquisition. 2. Determine the role of the IGF-1 ternary complex in skeletal growth and maintenance. 3. Define the mechanism/s by which circulating IGF-1 affects skeletal modeling and bone-turnover. We believe that the results of these studies will provide significant translational insight into understanding how circulating IGF-1 is a risk factor for a number of complex diseases including osteoporosis.

描述（由申请人提供）：之前的人体研究已经建立了血清 IGF-1 水平与骨矿物质密度 (BMD) 之间的相关性，并将血清 IGF-1 定义为骨折的危险因素。然而，这些研究主要集中在 BMD（骨生物学的一个不良指标）上，没有解释不同的骨特征（例如骨皮质和骨小梁）如何与血清 IGF-1 相关，也没有解释这些特征如何受血清 IGF-1 调节。 GH/IGF 轴的动物研究无法区分血清和局部 IGF-1 作用，因此很少有数据详细说明血清 IGF-1 及其复合物形成在确定骨性状结果中的重要性。解决这些问题需要对 IGF-1 传递成分进行基因剖析，因此需要使用独特的动物模型来调节 IGF-1 的传递，而不是 IGF-1 表达的整体变化或组织特异性变化。我们最近建立了两种血清 IGF-1 缺乏的小鼠模型，这使我们能够描述血清 IGF-1 水平及其传递系统对体内骨骼参数的影响；肝脏特异性 IGF-1 缺陷 (LID) 小鼠的血清 IGF-1 减少 80%，但肝外/骨骼组织中 IGF-1 表达正常，而 ALS 敲除 (ALSKO) 小鼠则由于三元复合物形成受损，血清 IGF-1 减少 60%，从而缩短了 IGF-1 半衰期。尽管血清 IGF-1 水平有类似的降低，但 LID 和 ALSKO 小鼠具有非常不同的骨骼表型。两种突变体均表现出 BMD 降低，但 LID 小鼠保留了骨小梁，而 ALSKO 小鼠的骨小梁体积显着减少。此外，与 LID 不同的是，ALSKO 小鼠对 PTH 没有合成代谢反应，破骨细胞生成受损，骨髓脂肪增多。因此，我们的假设是 IGF-1 传递复合物（与 ALS），而不是单独的循环 IGF-1，决定了骨骼的获得和重塑。我们建议 1. 确定循环 IGF-1 对骨骼获得峰值的影响程度。 2.确定IGF-1三元复合物在骨骼生长和维持中的作用。 3. 定义循环 IGF-1 影响骨骼建模和骨转换的机制。 我们相信，这些研究的结果将为理解循环 IGF-1 如何成为包括骨质疏松症在内的许多复杂疾病的危险因素提供重要的转化见解。