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

描述(申请人提供)：以前的人类研究已经确定了血清IGF-1水平与骨密度(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(一个糟糕的骨生物学指标)，没有解释不同的骨骼特征(如皮质骨和松质骨)如何与血清IGF-1相关，也没有解释这些特征如何受到血清IGF-1的调节。GH/IGF轴的动物研究不能区分血清和局部IGF-1的作用，因此很少有数据详细说明血清IGF-1及其复合体的形成在决定骨特征结果中的意义。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，而不是全局变化或组织特有的IGF-1表达变化。我们最近建立了两种血清IGF-1缺乏的小鼠模型，这两种模型允许我们描述血清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，其血清IGF-1水平下降80%，但在肝外/骨骼组织中IGF-1表达正常；ALS基因敲除(ALSKO)小鼠，由于三元复合体形成受阻，血清IGF-1水平下降60%，从而缩短IGF-1半衰期。尽管血清IGF-1水平有相似的降低，但LID和ALSKO小鼠具有非常不同的骨骼表型。两个突变体都显示出骨密度降低，然而，lid小鼠保留了他们的骨小梁，而alsko小鼠的骨小梁体积显著减少。此外，与LID不同的是，ALSKO小鼠对甲状旁腺素没有合成代谢反应，表现出破骨细胞生成受损，并增加了骨髓脂肪。因此，我们的假设是，IGF-1传递复合体(与肌萎缩侧索硬化症)，而不是循环的IGF-1，决定了骨骼的获得和重塑。我们建议1.确定循环中的IGF-1对骨骼获取峰值的影响程度。2.确定IGF-1三元复合体在骨骼生长和维持中的作用。3.明确循环胰岛素样生长因子-1影响骨骼模型和骨转换的机制/S。 我们相信，这些研究的结果将为理解循环中的IGF-1是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翻译洞察力。

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.