title: Unbound (bioavailable) IGF1 enhances somatic growth.
abstract: Understanding insulin-like growth factor-1 (IGF1) biology is of particular importance because, apart from its role in mediating growth, it plays key roles in cellular transformation, organ regeneration, immune function, development of the musculoskeletal system and aging. IGF1 bioactivity is modulated by its binding to IGF-binding proteins (IGFBPs) and the acid labile subunit (ALS), which are present in serum and tissues. To determine whether IGF1 binding to IGFBPs is necessary to facilitate normal growth and development, we used a gene-targeting approach and generated two novel knock-in mouse models of mutated IGF1, in which the native Igf1 gene was replaced by Des-Igf1 (KID mice) or R3-Igf1 (KIR mice). The KID and KIR mutant proteins have reduced affinity for the IGFBPs, and therefore present as unbound IGF1, or 'free IGF1'. We found that both KID and KIR mice have reduced serum IGF1 levels and a concomitant increase in serum growth hormone levels. Ternary complex formation of IGF1 with the IGFBPs and the ALS was markedly reduced in sera from KID and KIR mice compared with wild type. Both mutant mice showed increased body weight, body and bone lengths, and relative lean mass. We found selective organomegaly of the spleen, kidneys and uterus, enhanced mammary gland complexity, and increased skeletal acquisition. 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.
authors.affiliation: Division of Endocrinology, Diabetes and Bone Disease, Mount Sinai School of Medicine, New York, NY 10029, USA.
authors.forename: Sebastien
authors.initials: S
authors.lastname: Elis
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Wu
authors.forename: Hayden-William
authors.initials: HW
authors.lastname: Courtland
authors.forename: Dara
authors.initials: D
authors.lastname: Cannata
authors.forename: Hui
authors.initials: H
authors.lastname: Sun
authors.forename: Mordechay
authors.initials: M
authors.lastname: Beth-On
authors.forename: Chengyu
authors.initials: C
authors.lastname: Liu
authors.forename: Hector
authors.initials: H
authors.lastname: Jasper
authors.forename: Horacio
authors.initials: H
authors.lastname: Domené
authors.forename: Liliana
authors.initials: L
authors.lastname: Karabatas
authors.forename: Clara
authors.initials: C
authors.lastname: Guida
authors.forename: Jelena
authors.initials: J
authors.lastname: Basta-Pljakic
authors.forename: Luis
authors.initials: L
authors.lastname: Cardoso
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Rosen
authors.forename: Jan
authors.initials: J
authors.lastname: Frystyk
authors.forename: Shoshana
authors.initials: S
authors.lastname: Yakar
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D001682:Biological Availability; D049628:Body Size / Q000502:physiology; D001835:Body Weight / Q000502:physiology; D005260:Female; D055879:Gene Knock-In Techniques; D013006:Growth Hormone / Q000378:metabolism; D048788:Growth and Development; D007334:Insulin-Like Growth Factor I / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008321:Mammary Glands, Animal / Q000166:cytology / Q000254:growth & development; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D023421:Models, Animal; D008969:Molecular Sequence Data; D046912:Multiprotein Complexes / Q000097:blood; D009929:Organ Size / Q000502:physiology; D010012:Osteogenesis; D011485:Protein Binding; D014599:Uterus / Q000166:cytology / Q000254:growth & development
chemical_list: D046912:Multiprotein Complexes; D007334:Insulin-Like Growth Factor I; D013006:Growth Hormone