Ablation of hepatic production of the acid-labile subunit in Bovine-GH transgenic mice: Effects on organ and skeletal growth

Zhongbo Liu, Tianzhen Han, Shannon Fishman, James Butler, Tracy Zimmermann, Frederic Tremblay, Carole Harbison, Nidhi Agrawal, John J. Kopchick, Mitchell B. Schaffler, Shoshana Yakar

Research output: Research - peer-reviewArticle

Abstract

Growth hormone (GH) and insulinlike growth factor 1 (IGF-1) are anabolic hormones that facilitate somatic and skeletal growth and regulate metabolism via endocrine and autocrine/paracrine mechanisms. We hypothesized that excess tissue production of GH would protect skeletal growth and integrity in states of reduction in serum IGF-1 levels. To test our hypothesis, we used bovine GH (bGH) transgenic mice as a model of GH hypersecretion and ablated the liver-derived acid-labile subunit, which stabilizes IGF-1 complexes with IGF-binding protein-3 and -5 in circulation. We used a genetic approach to create bGH/als gene knockout (ALSKO) mice and small interfering RNA (siRNA) gene-silencing approach to reduce als or igf-1 gene expression. We found that in both models, decreased IGF-1 levels in serum were associated with decreased body and skeletal size of the bGH mice. Excess GH produced more robust bones but compromised mechanical properties in male mice. Excess GH production in tissues did not protect from trabecular bone loss in response to reductions in serum IGF-1 (in bGH/ALSKO or bGH mice treated with siRNAs). Reduced serum IGF-1 levels in the bGH mice did not alleviate the hyperinsulinemia and did not resolve liver or kidney pathologies that resulted from GH hypersecretion. We concluded that reduced serum IGF-1 levels decrease somatic and skeletal growth even in states of excess GH.

LanguageEnglish (US)
Pages2556-2571
Number of pages16
JournalEndocrinology
Volume158
Issue number8
DOIs
StatePublished - Aug 1 2017

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Transgenic Mice
Intercellular Signaling Peptides and Proteins
Acids
Liver
Growth
bovine growth hormone
Serum
Growth Hormone
Growth hormone excess
Gene Knockout Techniques
Insulin-Like Growth Factor Binding Protein 5
Insulin-Like Growth Factor Binding Protein 3
Hyperinsulinism
Body Size
Gene Silencing
RNA Interference
Knockout Mice
Small Interfering RNA
Hormones
Pathology

ASJC Scopus subject areas

  • Endocrinology

Cite this

Ablation of hepatic production of the acid-labile subunit in Bovine-GH transgenic mice : Effects on organ and skeletal growth. / Liu, Zhongbo; Han, Tianzhen; Fishman, Shannon; Butler, James; Zimmermann, Tracy; Tremblay, Frederic; Harbison, Carole; Agrawal, Nidhi; Kopchick, John J.; Schaffler, Mitchell B.; Yakar, Shoshana.

In: Endocrinology, Vol. 158, No. 8, 01.08.2017, p. 2556-2571.

Research output: Research - peer-reviewArticle

Liu, Z, Han, T, Fishman, S, Butler, J, Zimmermann, T, Tremblay, F, Harbison, C, Agrawal, N, Kopchick, JJ, Schaffler, MB & Yakar, S 2017, 'Ablation of hepatic production of the acid-labile subunit in Bovine-GH transgenic mice: Effects on organ and skeletal growth' Endocrinology, vol 158, no. 8, pp. 2556-2571. DOI: 10.1210/en.2016-1952
Liu Z, Han T, Fishman S, Butler J, Zimmermann T, Tremblay F et al. Ablation of hepatic production of the acid-labile subunit in Bovine-GH transgenic mice: Effects on organ and skeletal growth. Endocrinology. 2017 Aug 1;158(8):2556-2571. Available from, DOI: 10.1210/en.2016-1952
Liu, Zhongbo ; Han, Tianzhen ; Fishman, Shannon ; Butler, James ; Zimmermann, Tracy ; Tremblay, Frederic ; Harbison, Carole ; Agrawal, Nidhi ; Kopchick, John J. ; Schaffler, Mitchell B. ; Yakar, Shoshana. / Ablation of hepatic production of the acid-labile subunit in Bovine-GH transgenic mice : Effects on organ and skeletal growth. In: Endocrinology. 2017 ; Vol. 158, No. 8. pp. 2556-2571
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