Skeletal response of male mice to anabolic hormone therapy in the absence of the igfals gene

Oran D. Kennedy, Hui Sun, YingJie Wu, Hayden William Courtland, Garry A. Williams, Luis Cardoso, Jelena Basta-Pljakic, Mitchell B. Schaffler, Shoshana Yakar

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)987-999
Number of pages13
JournalEndocrinology
Volume155
Issue number3
DOIs
StatePublished - Mar 2014

Fingerprint

Insulin-Like Growth Factor I
Hormones
Knockout Mice
Genes
Bone and Bones
Acids
Therapeutics
Growth
Serum
Insulin-Like Growth Factor Binding Protein 5
Body Weight
Growth Disorders
Insulin-Like Growth Factor Binding Proteins
Insulin-Like Growth Factor Binding Protein 3
Bone Development
Bone Resorption
Osteogenesis
Weight Gain
Age Groups
Phenotype

ASJC Scopus subject areas

  • Endocrinology

Cite this

Kennedy, O. D., Sun, H., Wu, Y., Courtland, H. W., Williams, G. A., Cardoso, L., ... Yakar, S. (2014). Skeletal response of male mice to anabolic hormone therapy in the absence of the igfals gene. Endocrinology, 155(3), 987-999. https://doi.org/10.1210/en.2013-1819

Skeletal response of male mice to anabolic hormone therapy in the absence of the igfals gene. / Kennedy, Oran D.; Sun, Hui; Wu, YingJie; Courtland, Hayden William; Williams, Garry A.; Cardoso, Luis; Basta-Pljakic, Jelena; Schaffler, Mitchell B.; Yakar, Shoshana.

In: Endocrinology, Vol. 155, No. 3, 03.2014, p. 987-999.

Research output: Contribution to journalArticle

Kennedy, OD, Sun, H, Wu, Y, Courtland, HW, Williams, GA, Cardoso, L, Basta-Pljakic, J, Schaffler, MB & Yakar, S 2014, 'Skeletal response of male mice to anabolic hormone therapy in the absence of the igfals gene', Endocrinology, vol. 155, no. 3, pp. 987-999. https://doi.org/10.1210/en.2013-1819
Kennedy OD, Sun H, Wu Y, Courtland HW, Williams GA, Cardoso L et al. Skeletal response of male mice to anabolic hormone therapy in the absence of the igfals gene. Endocrinology. 2014 Mar;155(3):987-999. https://doi.org/10.1210/en.2013-1819
Kennedy, Oran D. ; Sun, Hui ; Wu, YingJie ; Courtland, Hayden William ; Williams, Garry A. ; Cardoso, Luis ; Basta-Pljakic, Jelena ; Schaffler, Mitchell B. ; Yakar, Shoshana. / Skeletal response of male mice to anabolic hormone therapy in the absence of the igfals gene. In: Endocrinology. 2014 ; Vol. 155, No. 3. pp. 987-999.
@article{3f6d89d9d03049f29c413394b1e55602,
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.",
author = "Kennedy, {Oran D.} and Hui Sun and YingJie Wu and Courtland, {Hayden William} and Williams, {Garry A.} and Luis Cardoso and Jelena Basta-Pljakic and Schaffler, {Mitchell B.} and Shoshana Yakar",
year = "2014",
month = "3",
doi = "10.1210/en.2013-1819",
language = "English (US)",
volume = "155",
pages = "987--999",
journal = "Endocrinology",
issn = "0013-7227",
publisher = "The Endocrine Society",
number = "3",

}

TY - JOUR

T1 - Skeletal response of male mice to anabolic hormone therapy in the absence of the igfals gene

AU - Kennedy, Oran D.

AU - Sun, Hui

AU - Wu, YingJie

AU - Courtland, Hayden William

AU - Williams, Garry A.

AU - Cardoso, Luis

AU - Basta-Pljakic, Jelena

AU - Schaffler, Mitchell B.

AU - Yakar, Shoshana

PY - 2014/3

Y1 - 2014/3

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84896875101&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84896875101&partnerID=8YFLogxK

U2 - 10.1210/en.2013-1819

DO - 10.1210/en.2013-1819

M3 - Article

VL - 155

SP - 987

EP - 999

JO - Endocrinology

JF - Endocrinology

SN - 0013-7227

IS - 3

ER -