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

描述（由申请人提供）：先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定义为骨折的风险因素。然而，这些研究主要集中在BMD（骨生物学的不良指标）上，没有解释不同的骨性状（如皮质骨和小梁骨）如何与血清IGF-1相关，也没有解释这些性状如何受血清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意义。解决这些问题需要对IGF-1递送组分进行遗传解剖，因此需要使用独特的动物模型来调节IGF-1的递送，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水平及其递送系统对体内骨骼参数的影响;血清IGF-1降低80%但肝外/骨骼组织中IGF-1表达正常的肝特异性IGF-1缺陷（LID）小鼠，以及ALS敲除（ALSKO）小鼠，其由于三元复合物形成受损而显示血清IGF-1降低60%，从而缩短IGF-1半衰期。尽管血清IGF-1水平降低相似，但LID和ALSKO小鼠具有非常不同的骨骼表型。两种突变体均显示BMD降低，然而，LID小鼠保留其骨小梁，而ALSKO小鼠的骨小梁体积显著降低。此外，与LID不同，ALSKO小鼠对PTH没有合成代谢反应，破骨细胞生成受损，骨髓肥胖增加。因此，我们的假设是，IGF-1传递复合物（与ALS），而不是单独循环IGF-1，决定骨骼获得和重塑。我们建议1.确定循环IGF-1影响峰值骨骼获取的程度。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风险因素提供重要的翻译见解。

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.