title: The ternary IGF complex influences postnatal bone acquisition and the skeletal response to intermittent parathyroid hormone.
abstract: The role of circulating IGF-I in skeletal acquisition and the anabolic response to PTH is not well understood. We generated IGF-I-deficient mice by gene deletions of IGF ternary complex components including: (1) liver-specific deletion of the IGF-I gene (LID), (2) global deletion of the acid-labile (ALS) gene (ALSKO), and (3) both liver IGF-I and ALS inactivated genes (LA). Twelve-week-old male control (CTL), LID, ALSKO, and LA mice were treated with vehicle (VEH) or human PTH(1-34) for 4 weeks. VEH-treated IGF-I-deficient mice (i.e. LID, ALSKO and LA mice) exhibited reduced cortical cross-sectional area (P = 0.001) compared with CTL mice; in contrast, femoral trabecular bone volume fractions (BV/TV) of the IGF-I-deficient mice were consistently greater than CTL (P < 0.01). ALSKO mice exhibited markedly reduced osteoblast number and surface (P < 0.05), as well as mineral apposition rate compared with other IGF-I-deficient and CTL mice. Adherent bone marrow stromal cells, cultured in beta-glycerol phosphate and ascorbic acid, showed no strain differences in secreted IGF-I. In response to PTH, there were both compartment- and strain-specific effects. Cortical bone area was increased by PTH in CTL and ALSKO mice, but not in LID or LA mice. In the trabecular compartment, PTH increased femoral and vertebral BV/TV in LID, but not in ALSKO or LA mice. In conclusion, we demonstrated that the presentation of IGF-I as a circulating complex is essential for skeletal remodeling and the anabolic response to PTH. We postulate that the ternary complex itself, rather than IGF-I alone, influences bone acquisition in a compartment-specific manner (i.e. cortical vs trabecular bone).
authors.affiliation: National Institute of Diabetes, Digestive and Kidney Diseases, Bethesda, Maryland, USA.
authors.forename: Shoshana
authors.initials: S
authors.lastname: Yakar
authors.forename: Mary L
authors.initials: ML
authors.lastname: Bouxsein
authors.forename: Ernesto
authors.initials: E
authors.lastname: Canalis
authors.forename: Hui
authors.initials: H
authors.lastname: Sun
authors.forename: Vaida
authors.initials: V
authors.lastname: Glatt
authors.forename: Caren
authors.initials: C
authors.lastname: Gundberg
authors.forename: Pinchas
authors.initials: P
authors.lastname: Cohen
authors.forename: David
authors.initials: D
authors.lastname: Hwang
authors.forename: Yves
authors.initials: Y
authors.lastname: Boisclair
authors.forename: Derek
authors.initials: D
authors.lastname: Leroith
authors.forename: Clifford J
authors.initials: CJ
authors.lastname: Rosen
mesh_terms: D000818:Animals; D015519:Bone Density / Q000502:physiology; D001854:Bone Marrow Cells / Q000502:physiology; D016723:Bone Remodeling / Q000502:physiology; D002352:Carrier Proteins / Q000235:genetics; D002452:Cell Count; D002478:Cells, Cultured; D005269:Femur / Q000033:anatomy & histology; D017353:Gene Deletion; D006023:Glycoproteins / Q000235:genetics; D007279:Injections, Subcutaneous; D018971:Insulin-Like Growth Factor Binding Protein 2 / Q000097:blood; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D007334:Insulin-Like Growth Factor I / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008099:Liver / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000502:physiology; D015675:Osteocalcin / Q000097:blood; D010012:Osteogenesis / Q000502:physiology*; D010281:Parathyroid Hormone / Q000008:administration & dosage / Q000378:metabolism*; D010446:Peptide Fragments / Q000008:administration & dosage; D013131:Spine; D017154:Stromal Cells / Q000502:physiology
chemical_list: D002352:Carrier Proteins; D006023:Glycoproteins; D018971:Insulin-Like Growth Factor Binding Protein 2; D018972:Insulin-Like Growth Factor Binding Protein 3; D010281:Parathyroid Hormone; D010446:Peptide Fragments; C075944:insulin-like growth factor binding protein, acid labile subunit; D015675:Osteocalcin; D007334:Insulin-Like Growth Factor I