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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR054919-03
Application #
7659674
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Sharrock, William J
Project Start
2007-09-15
Project End
2012-07-31
Budget Start
2009-08-01
Budget End
2010-07-31
Support Year
3
Fiscal Year
2009
Total Cost
$357,269
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
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Gong, Zhenwei; Kennedy, Oran; Sun, Hui et al. (2014) Reductions in serum IGF-1 during aging impair health span. Aging Cell 13:408-18
Gallagher, Emily Jane; Sun, Hui; Kornhauser, Caroline et al. (2014) The effect of dipeptidyl peptidase-IV inhibition on bone in a mouse model of type 2 diabetes. Diabetes Metab Res Rev 30:191-200
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Courtland, Hayden-William; Kennedy, Oran D; Wu, Yingjie et al. (2013) Low levels of plasma IGF-1 inhibit intracortical bone remodeling during aging. Age (Dordr) 35:1691-703
Wu, Yingjie; Sun, Hui; Basta-Pljakic, Jelena et al. (2013) Serum IGF-1 is insufficient to restore skeletal size in the total absence of the growth hormone receptor. J Bone Miner Res 28:1575-86
Yakar, Shoshana; Adamo, Martin L (2012) Insulin-like growth factor 1 physiology: lessons from mouse models. Endocrinol Metab Clin North Am 41:231-47, v
Elis, Sebastien; Wu, YingJie; Courtland, Hayden-William et al. (2011) Increased serum IGF-1 levels protect the musculoskeletal system but are associated with elevated oxidative stress markers and increased mortality independent of tissue igf1 gene expression. Aging Cell 10:547-50
Landau, Daniel; Biada, Jaclyn; Chen, Yu et al. (2011) A marked deficiency in circulating and renal IGF-I peptide does not inhibit compensatory renal enlargement in uninephrectomized mice. Growth Horm IGF Res 21:279-84
Courtland, Hayden-William; Sun, Hui; Beth-On, Mordechay et al. (2011) Growth hormone mediates pubertal skeletal development independent of hepatic IGF-1 production. J Bone Miner Res 26:761-8

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