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

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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.