title: Skeletal response of male mice to anabolic hormone therapy in the absence of the Igfals gene.
abstract: IGF-I is a critical regulator of skeletal acquisition, which acts in endocrine and autocrine/paracrine modes. In serum, IGF-I is carried by the IGF-binding proteins in binary complexes. Further stabilization of these complexes is achieved by binding to the acid labile subunit (ALS) in a ternary complex (of IGF-I-IGF-binding protein 3/5-ALS). Ablation of the Igfals gene in humans (ALS deficiency) and mice (ALS knockout [ALSKO]) leads to markedly decreased serum IGF-I levels, growth retardation, and impaired skeletal acquisition. To investigate whether hormonal replacement therapy would improve the skeletal phenotype in cases of Igfals gene ablation, we treated male ALSKO mice with GH, IGF-I, or a combination of both. Treatments were administered to animals between 4 and 16 weeks of age or from 8 to 16 weeks of age. Although all treatment groups showed an increase (20%) in serum IGF-I levels, there was no increase in body weight, weight gain, or bone length in either age group. Despite the blunted linear growth in response to hormone therapy, ALSKO mice treated with GH showed radial bone growth, which contributed to bone strength tested by 4-point bending. We found that ALSKO mice treated with GH showed increased total cross-sectional area, cortical bone area, and cortical thickness by microtomography. Dynamic histomorphometry showed that although GH and double treatment groups resulted in trends towards increased bone formation parameters, these did not reach significance. However, bone resorption parameters were significantly increased in all treatment groups. ALSKO mice treated between 4 and 16 weeks of age showed minor differences in bone traits compared with vehicle-treated mice. In conclusion, treatment with GH and IGF-I do not work synergistically to rescue the stunted growth found in mice lacking the Igfals gene. Although GH alone appears to increase bone parameters slightly, it does not affect body weight or linear growth.
authors.affiliation: 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.
authors.forename: Oran D
authors.initials: OD
authors.lastname: Kennedy
authors.forename: Hui
authors.initials: H
authors.lastname: Sun
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Wu
authors.forename: Hayden-William
authors.initials: HW
authors.lastname: Courtland
authors.forename: Garry A
authors.initials: GA
authors.lastname: Williams
authors.forename: Luis
authors.initials: L
authors.lastname: Cardoso
authors.forename: Jelena
authors.initials: J
authors.lastname: Basta-Pljakic
authors.forename: Mitchell B
authors.initials: MB
authors.lastname: Schaffler
authors.forename: Shoshana
authors.initials: S
authors.lastname: Yakar
mesh_terms: D045930:Anabolic Agents / Q000378:metabolism*; D000818:Animals; D001835:Body Weight; D015519:Bone Density / Q000187:drug effects; D001846:Bone Development / Q000187:drug effects / Q000502:physiology; D001842:Bone and Bones / Q000187:drug effects* / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics* / Q000502:physiology*; D003433:Crosses, Genetic; D005951:Glucose Tolerance Test; D006023:Glycoproteins / Q000235:genetics* / Q000502:physiology*; D006728:Hormones / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009929:Organ Size; D010641:Phenotype; D011485:Protein Binding; D013997:Time Factors; D055114:X-Ray Microtomography
chemical_list: D045930:Anabolic Agents; D002352:Carrier Proteins; D006023:Glycoproteins; D006728:Hormones; D007328:Insulin; D018972:Insulin-Like Growth Factor Binding Protein 3; C075944:insulin-like growth factor binding protein, acid labile subunit; D007334:Insulin-Like Growth Factor I