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

Summary

Principal Investigator: Shoshana Yakar
Affiliation: Mount Sinai School of Medicine
Country: USA
Abstract: 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.
Funding Period: 2007-09-15 - 2012-07-31
more information: NIH RePORT

Top Publications

  1. ncbi Serum complexes of insulin-like growth factor-1 modulate skeletal integrity and carbohydrate metabolism
    Shoshana Yakar
    Endocrinology Diabetes and Bone Disease, The Mt Sinai School of Medicine, One Gustave L Levy Place, Box 1055, New York, NY 10029 6574, USA
    FASEB J 23:709-19. 2009
  2. ncbi Type 2 diabetic mice demonstrate slender long bones with increased fragility secondary to increased osteoclastogenesis
    Yuki Kawashima
    Division of Endocrinology, Diabetes and Bone Diseases, Mount Sinai School of Medicine, New York, NY 10029, USA
    Bone 44:648-55. 2009
  3. ncbi Serum IGF-1 determines skeletal strength by regulating subperiosteal expansion and trait interactions
    Shoshana Yakar
    Division of Endocrinology, Diabetes and Bone Disease, Mount Sinai School of Medicine, New York, New York 10029 6574, USA
    J Bone Miner Res 24:1481-92. 2009
  4. ncbi Elevated levels of insulin-like growth factor (IGF)-I in serum rescue the severe growth retardation of IGF-I null mice
    Yingjie Wu
    Division of Endocrinology, Diabetes, and Bone Disease, Mount Sinai School of Medicine, New York, New York 10029 6574, USA
    Endocrinology 150:4395-403. 2009
  5. ncbi High-efficient FLPo deleter mice in C57BL/6J background
    Yingjie Wu
    Endocrinology Diabetes and Bone Disease Division, Mount Sinai School of Medicine, New York, New York, United States of America
    PLoS ONE 4:e8054. 2009
  6. ncbi The insulin-like growth factor-1 binding protein acid-labile subunit alters mesenchymal stromal cell fate
    J Christopher Fritton
    Division of Endocrinology, Diabetes and Bone Disease, Mount Sinai School of Medicine, New York, New York 10029, USA
    J Biol Chem 285:4709-14. 2010

Scientific Experts

  • Shoshana Yakar
  • Yuki Kawashima
  • Yingjie Wu
  • Hui Sun
  • J Christopher Fritton
  • Derek LeRoith
  • Yinjgie Wu
  • Sebastien Elis
  • Clifford J Rosen
  • Hayden Williams Courtland
  • Wilson Mejia
  • David Clemmons
  • Chunxin Wang

Detail Information

Publications6

  1. ncbi Serum complexes of insulin-like growth factor-1 modulate skeletal integrity and carbohydrate metabolism
    Shoshana Yakar
    Endocrinology Diabetes and Bone Disease, The Mt Sinai School of Medicine, One Gustave L Levy Place, Box 1055, New York, NY 10029 6574, USA
    FASEB J 23:709-19. 2009
    ..3) IGFBP-3 deficiency resulted in increased linear growth. In summary, each IGF-1 complex constituent appears to play a distinct role in determining skeletal phenotype, with different effects on cortical and trabecular bone compartments...
  2. ncbi Type 2 diabetic mice demonstrate slender long bones with increased fragility secondary to increased osteoclastogenesis
    Yuki Kawashima
    Division of Endocrinology, Diabetes and Bone Diseases, Mount Sinai School of Medicine, New York, NY 10029, USA
    Bone 44:648-55. 2009
    ..Further, these results emphasize the importance of evaluating diabetic bone based on morphology in addition to bone mass...
  3. ncbi Serum IGF-1 determines skeletal strength by regulating subperiosteal expansion and trait interactions
    Shoshana Yakar
    Division of Endocrinology, Diabetes and Bone Disease, Mount Sinai School of Medicine, New York, New York 10029 6574, USA
    J Bone Miner Res 24:1481-92. 2009
    ....
  4. ncbi Elevated levels of insulin-like growth factor (IGF)-I in serum rescue the severe growth retardation of IGF-I null mice
    Yingjie Wu
    Division of Endocrinology, Diabetes, and Bone Disease, Mount Sinai School of Medicine, New York, New York 10029 6574, USA
    Endocrinology 150:4395-403. 2009
    ..Furthermore, we show that tissue IGF-I is necessary for the development of the female reproductive system and cannot be compensated by elevated levels of serum IGF-I...
  5. ncbi High-efficient FLPo deleter mice in C57BL/6J background
    Yingjie Wu
    Endocrinology Diabetes and Bone Disease Division, Mount Sinai School of Medicine, New York, New York, United States of America
    PLoS ONE 4:e8054. 2009
    ..Our new FLPo transgenic mice (on pure C57BJ/6 background) will largely facilitate the gene targeting process and is valuable for conditional gene manipulation...
  6. ncbi The insulin-like growth factor-1 binding protein acid-labile subunit alters mesenchymal stromal cell fate
    J Christopher Fritton
    Division of Endocrinology, Diabetes and Bone Disease, Mount Sinai School of Medicine, New York, New York 10029, USA
    J Biol Chem 285:4709-14. 2010
    ....