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Serum complexes of insulin-like growth factor-1 modulate skeletal integrity and carbohydrate metabolism

Shoshana Yakar^*,1, Clifford J. Rosen, Mary L. Bouxsein, Hui Sun^*, Wilson Mejia^*, Yuki Kawashima^*, Yingjie Wu^*, Kelly Emerton^*, Valerie Williams^*, Karl Jepsen^*, Mitchell B. Schaffler^*, Robert J. Majeska^*, Oksana Gavrilova, Mariana Gutierrez^||, David Hwang^¶, Patricia Pennisi, Jan Frystyk^#, Yves Boisclair^**, John Pintar, Héctor Jasper^||, Horacio Domene^||, Pinchas Cohen^¶, David Clemmons and Derek LeRoith^*

^* Endocrine and Orthopedics Divisions, Mount Sinai School of Medicine, New York, New York, USA;

Maine Medical Center Research Institute, Scarborough, Maine, USA;

Orthopedic Biomechanics Laboratory, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA;

Metabolic Core, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland USA;

^|| Endocrinology Research Center, Division of Endocrinology, R. Gutierrez Children’s Hospital, Buenos Aires, Argentina;

^¶ Division of Pediatric Endocrinology, Mattel Hospital for Children, David Geffen School of Medicine, Los Angeles California, USA;

^# Medical Research Laboratories, Clinical Institute and Medical Department M (Diabetes and Endocrinology), Aarhus University Hospital, Norrebrogade, Aarhus, Denmark;

^** The Department of Animal Science, Cornell University, Ithaca, New York, USA;

Department of Neuroscience and Cell Biology, University of Medicine and Dentistry of New Jersey, Piscataway, New Jersey, USA; and

Division of Endocrinology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

¹Correspondence: Endocrinology/Diabetes and Bone Disease, The Mt. Sinai School of Medicine, One Gustave L Levy Place, Box 1055, New York, NY 10029-6574, USA. E-mail: shoshana.yakar{at}mssm.edu

Serum insulin-like growth factor (IGF) -1 is secreted mainly by the liver and circulates bound to IGF-binding proteins (IGFBPs), either as binary complexes or ternary complexes with IGFBP-3 or IGFBP-5 and an acid-labile subunit (ALS). The purpose of this study was to genetically dissect the role of IGF-1 circulatory complexes in somatic growth, skeletal integrity, and metabolism. Phenotypic comparisons of controls and four mouse lines with genetic IGF-1 deficits—liver-specific IGF-1 deficiency (LID), ALS knockout (ALSKO), IGFBP-3 (BP3) knockout, and a triply deficient LID/ALSKO/BP3 line—produced several novel findings. 1) All deficient strains had decreased serum IGF-1 levels, but this neither predicted growth potential or skeletal integrity nor defined growth hormone secretion or metabolic abnormalities. 2) IGF-1 deficiency affected development of both cortical and trabecular bone differently, effects apparently dependent on the presence of different circulating IGF-1 complexes. 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.—Yakar, S., Rosen, C. J., Bouxsein, M. L., Sun, H., Mejia, W., Kawashima, Y., Wu, Y., Emerton, K., Williams, V., Jepsen, K., Schaffler, M. B., Majeska, R. J., Gavrilova, O., Gutierrez, M., Hwang, D., Pennisi, P., Frystyk, J., Boisclair, Y., Pintar, J., Jasper, H., Domene, H., Cohen, P., Clemmons, D., LeRoith, D. Serum complexes of insulin-like growth factor-1 modulate skeletal integrity and carbohydrate metabolism.

Key Words: cortical bone • trabecular bone • osteoblast • osteoclast • ternary complex • binary complex

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