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. pmc Skeletal response of male mice to anabolic hormone therapy in the absence of the Igfals gene
    Oran D Kennedy
    Department of Biomedical Engineering O D K, L C, J B P, M B S, City College of New York, New York 10031 David B Kriser Dental Center H S, Y W, G A W, S Y, Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, New York 10010 4086 and Division of Endocrinology H W C, S Y, Diabetes and Bone Disease, Mount Sinai School of Medicine, New York, New York 10029 6547
    Endocrinology 155:987-99. 2014
  2. ncbi Reductions in serum IGF-1 during aging impair health span
    Zhenwei Gong
    Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York, 10461, USA
    Aging Cell 13:408-18. 2014
  3. pmc Serum IGF-1 is insufficient to restore skeletal size in the total absence of the growth hormone receptor
    Yingjie Wu
    David B Kriser Dental Center, Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, NY, USA
    J Bone Miner Res 28:1575-86. 2013
  4. pmc Low levels of plasma IGF-1 inhibit intracortical bone remodeling during aging
    Hayden William Courtland
    Division of Endocrinology, Diabetes and Bone Diseases, Mount Sinai School of Medicine, New York, NY, 10029, USA
    Age (Dordr) 35:1691-703. 2013
  5. pmc Unbound (bioavailable) IGF1 enhances somatic growth
    Sebastien Elis
    Division of Endocrinology, Diabetes and Bone Disease, Mount Sinai School of Medicine, New York, NY 10029, USA
    Dis Model Mech 4:649-58. 2011
  6. pmc 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
    Sebastien Elis
    Mount Sinai School of Medicine, New York, NY 10029, USA
    Aging Cell 10:547-50. 2011
  7. pmc Growth hormone mediates pubertal skeletal development independent of hepatic IGF-1 production
    Hayden William Courtland
    Division of Endocrinology, Diabetes and Bone Diseases, Mount Sinai School of Medicine, New York, NY 10029 6574, USA
    J Bone Miner Res 26:761-8. 2011
  8. pmc IGF-1 and bone: New discoveries from mouse models
    Shoshana Yakar
    Division of Endocrinology, University of North Carolina, Chapel Hill, NC, USA
    J Bone Miner Res 25:2543-52. 2010
  9. pmc Sex-specific regulation of body size and bone slenderness by the acid labile subunit
    Hayden William Courtland
    Division of Endocrinology, Diabetes and Bone Diseases, Mount Sinai School of Medicine, New York, NY 10029 6574, USA
    J Bone Miner Res 25:2059-68. 2010
  10. pmc Elevated serum IGF-1 levels synergize PTH action on the skeleton only when the tissue IGF-1 axis is intact
    Sebastien Elis
    Division of Endocrinology, Diabetes and Bone Disease, Mount Sinai School of Medicine, New York, NY 10029 6574, USA
    J Bone Miner Res 25:2051-8. 2010

Scientific Experts

  • Shoshana Yakar
  • Yuki Kawashima
  • Yingjie Wu
  • Hui Sun
  • Hayden William Courtland
  • Sebastien Elis
  • Clifford J Rosen
  • Mitchell B Schaffler
  • J Christopher Fritton
  • Oran D Kennedy
  • Luis Cardoso
  • Jelena Basta-Pljakic
  • Derek LeRoith
  • Garry A Williams
  • Zhenwei Gong
  • Martin L Adamo
  • Horacio Domene
  • Liliana Karabatas
  • Clara Guida
  • Hector Jasper
  • Mordechay Beth-On
  • Archana Vijayakumar
  • Robert J Majeska
  • Wilson Mejia
  • Oran Kennedy
  • Roger P Farrar
  • Ronald W Matheny
  • Gene B Hubbard
  • Yuji Ikeno
  • Laura Klein
  • Radhika H Muzumdar
  • Ying Gao
  • Jan Frystyk
  • Chengyu Liu
  • Dara Cannata
  • Yinjgie Wu
  • Mary Bouxsein
  • Kelly B Emerton
  • Karl J Jepsen
  • Hayden Williams Courtland
  • David Panus
  • David Clemmons
  • Jane Maynard
  • Victoria DeMambro
  • Clifford Rosen
  • Ruslan Novosyadlyy
  • Chunxin Wang

Detail Information

Publications19

  1. pmc Skeletal response of male mice to anabolic hormone therapy in the absence of the Igfals gene
    Oran D Kennedy
    Department of Biomedical Engineering O D K, L C, J B P, M B S, City College of New York, New York 10031 David B Kriser Dental Center H S, Y W, G A W, S Y, Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, New York 10010 4086 and Division of Endocrinology H W C, S Y, Diabetes and Bone Disease, Mount Sinai School of Medicine, New York, New York 10029 6547
    Endocrinology 155:987-99. 2014
    ..Although GH alone appears to increase bone parameters slightly, it does not affect body weight or linear growth. ..
  2. ncbi Reductions in serum IGF-1 during aging impair health span
    Zhenwei Gong
    Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York, 10461, USA
    Aging Cell 13:408-18. 2014
    ..We conclude that an intact GH/IGF-1 axis is essential to maintain health span and that elevated GH, even late in life, associates with increased pathology...
  3. pmc Serum IGF-1 is insufficient to restore skeletal size in the total absence of the growth hormone receptor
    Yingjie Wu
    David B Kriser Dental Center, Department of Basic Science and Craniofacial Biology, New York University College of Dentistry, New York, NY, USA
    J Bone Miner Res 28:1575-86. 2013
    ..These findings are consistent with clinical data showing that IGF-I replacement therapy in patients with Laron syndrome does not achieve full skeletal growth...
  4. pmc Low levels of plasma IGF-1 inhibit intracortical bone remodeling during aging
    Hayden William Courtland
    Division of Endocrinology, Diabetes and Bone Diseases, Mount Sinai School of Medicine, New York, NY, 10029, USA
    Age (Dordr) 35:1691-703. 2013
    ..We show here that lifelong reductions in serum IGF-1 compromise skeletal size in development leading to slender bones; they are also associated with decreased intracortical bone remodeling and preservation of bone strength during aging. ..
  5. pmc Unbound (bioavailable) IGF1 enhances somatic growth
    Sebastien Elis
    Division of Endocrinology, Diabetes and Bone Disease, Mount Sinai School of Medicine, New York, NY 10029, USA
    Dis Model Mech 4:649-58. 2011
    ..The KID and KIR models show unequivocally that IGF1-complex formation with the IGFBPs is fundamental for establishing normal body and organ size, and that uncontrolled IGF bioactivity could lead to pathological conditions...
  6. pmc 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
    Sebastien Elis
    Mount Sinai School of Medicine, New York, NY 10029, USA
    Aging Cell 10:547-50. 2011
    ..Additionally, in male KO-HIT mice, increases in serum IGF-1 levels were insufficient to protect against age-related muscle loss...
  7. pmc Growth hormone mediates pubertal skeletal development independent of hepatic IGF-1 production
    Hayden William Courtland
    Division of Endocrinology, Diabetes and Bone Diseases, Mount Sinai School of Medicine, New York, NY 10029 6574, USA
    J Bone Miner Res 26:761-8. 2011
    ....
  8. pmc IGF-1 and bone: New discoveries from mouse models
    Shoshana Yakar
    Division of Endocrinology, University of North Carolina, Chapel Hill, NC, USA
    J Bone Miner Res 25:2543-52. 2010
    ..In this review we present new and old findings from mouse models of the IGF system and discuss their clinical relevance to normal and pathological skeletal physiology...
  9. pmc Sex-specific regulation of body size and bone slenderness by the acid labile subunit
    Hayden William Courtland
    Division of Endocrinology, Diabetes and Bone Diseases, Mount Sinai School of Medicine, New York, NY 10029 6574, USA
    J Bone Miner Res 25:2059-68. 2010
    ..This study revealed age- and sex-specific dependencies of body size and bone size on the ALS. These findings may explain the heterogeneity in growth and BMD measurements reported in human ALS-deficient patients...
  10. pmc Elevated serum IGF-1 levels synergize PTH action on the skeleton only when the tissue IGF-1 axis is intact
    Sebastien Elis
    Division of Endocrinology, Diabetes and Bone Disease, Mount Sinai School of Medicine, New York, NY 10029 6574, USA
    J Bone Miner Res 25:2051-8. 2010
    ..Thus enhancement of PTH anabolic actions depends on tissue IGF-1...
  11. pmc Elevated serum levels of IGF-1 are sufficient to establish normal body size and skeletal properties even in the absence of tissue IGF-1
    Sebastien Elis
    Division of Endocrinology, Diabetes and Bone Disease, Mount Sinai School of Medicine, New York, NY 10029 6574, USA
    J Bone Miner Res 25:1257-66. 2010
    ..Our data indicate that in the absence of tissue igf1 gene expression, maintaining long-term elevations in serum IGF-1 is sufficient to establish normal body size, body composition, and both skeletal architecture and mechanical function...
  12. pmc Biological effects of growth hormone on carbohydrate and lipid metabolism
    Archana Vijayakumar
    Division of Endocrinology, Diabetes and Bone Diseases, The Samuel Bronfman Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA
    Growth Horm IGF Res 20:1-7. 2010
    ..questions that still remain to be answered are (i) What are the molecular mechanisms by which GH regulates substrate metabolism? (ii) Does GH affect substrate metabolism directly or indirectly via IGF-1 or antagonism of insulin action?..
  13. pmc Growth hormone protects against ovariectomy-induced bone loss in states of low circulating insulin-like growth factor (IGF-1)
    J Christopher Fritton
    Leni and Peter W May Department of Orthopaedics, Mount Sinai School of Medicine, New York, NY 10029, USA
    J Bone Miner Res 25:235-46. 2010
    ..Interactions between estrogen and the GH/IGF-1 system as related to bone remodeling provide a pathway to minimize degeneration of bone tissue structure and osteoporotic fracture...
  14. pmc 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
    ....
  15. pmc 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...
  16. pmc 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...
  17. pmc 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
    ....
  18. pmc 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...
  19. pmc 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...