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

描述（由申请人提供）：先前的人类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骨密度（一个较差的骨生物学指标）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的作用，因此很少有数据详细说明血清IGF-1及其复合物在决定骨性状结果中的重要性。解决这些问题需要对IGF-1传递成分进行遗传解剖，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表达的全局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，血清IGF-1减少80%，但肝外/骨骼组织中IGF-1表达正常；ALS敲除（ALSKO）小鼠，由于三元复合物形成受损，血清IGF-1减少60%，从而缩短IGF-1半衰期。尽管血清IGF-1水平降低相似，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骨密度降低，然而，LID小鼠保留了其小梁骨，而ALSKO小鼠的小梁骨体积显著减少。此外，与lid不同，ALSKO小鼠对甲状旁腺激素没有合成代谢反应，破骨细胞生成受损，骨髓脂肪增加。因此，我们的假设是IGF-1递送复合物（ALS），而不是单独循环IGF-1，决定骨骼获得和重塑。我们提议……确定循环IGF-1对骨骼峰值获得的影响程度。2. 确定IGF-1三元复合物在骨骼生长和维持中的作用。3. 明确循环IGF-1影响骨骼建模和骨转换的机制。

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.