Growth hormone (GH) receptors, binding proteins and IGF-I concentrations in the serum of transgenic mice expressing bovine GH agonist or antagonist

Sotelo, Ana I.; Bartke, Andrzej; Kopchick, John J.; Knapp, J.R.; Turyn, Daniel

doi:10.1677/joe.0.1580053

Cited by 24 publications

(18 citation statements)

References 23 publications

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“…Our study may represent a compensatory upregulation of the GHR gene expression in response to the functional blockade of the GHR by the GHRA. However, in contrast to our findings, Chen et al (1997) using GHRA expressing transgenic mice did not observe increased hepatic GHR/GHBP mRNA expression although strongly enhanced liver GHR and serum GHBP protein levels were found in these same GHRA transgenic animals (Chen et al 1997, Sotelo et al 1998.…”

Section: Discussioncontrasting

confidence: 99%

Dose-response effects of a new growth hormone receptor antagonist (B2036-PEG) on circulating, hepatic and renal expression of the growth hormone/insulin-like growth factor system in adult mice

Neck¹,

Dits²,

Cingel³

et al. 2000

Journal of Endocrinology

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The effects of growth hormone (GH) in regulating the expression of the hepatic and renal GH and insulin-like growth factor (IGF) system were studied by administering a novel GH receptor antagonist (GHRA) (B2036-PEG) at different doses (0, 1·25, 2·5, 5 and 10 mg/kg/day) to mice for 7 days. No differences were observed in the groups with respect to body weight, food consumption or blood glucose. However, a dose-dependent decrease was observed in circulating IGF-I levels and in hepatic and renal IGF-I levels at the highest doses. In contrast, in the 5 and 10 mg/kg/day GHRA groups, circulating and hepatic transcriptional IGF binding protein-3 (IGFBP-3) levels were not modified, likely resulting in a significantly decreased IGF-I/IGFBP-3 ratio. Hepatic GH receptor (GHR) and GH binding protein (GHBP) mRNA levels increased significantly in all GHRA dosage groups. Endogenous circulatory GH levels increased significantly in the 2·5 and 5 mg/kg/day GHRA groups. Remarkably, increased circulating IGFBP-4 and hepatic IGFBP-4 mRNA levels were observed in all GHRA administration groups. Renal GHR and GHBP mRNA levels were not modified by GHRA administration at the highest doses. Also, renal IGFBP-3 mRNA levels remained unchanged in most GHRA administration groups, whereas IGFBP-1, -4 and -5 mRNA levels were significantly increased in the 5 and 10 mg/kg/day GHRA administration groups.In conclusion, the effects of a specific GHR blockade on circulating, hepatic and renal GH/IGF axis reported here, may prove useful in the future clinical use of GHRAs.

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Section: Discussioncontrasting

confidence: 99%

Dose-response effects of a new growth hormone receptor antagonist (B2036-PEG) on circulating, hepatic and renal expression of the growth hormone/insulin-like growth factor system in adult mice

Neck¹,

Dits²,

Cingel³

et al. 2000

Journal of Endocrinology

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“…In three mixed murine strains used for transgenic studies, controls had IGF-I levels of 500-900 ng/mL at 6 weeks of age [17]. Significantly lower levels of $250 ng/ mL have been reported [18], but ages were not specified in these studies. IGF-I levels of $900 ng/mL have been reported in male and female CD-1 mice at 5 months [19]; nearly twofold higher than those observed in our studies.…”

Section: Discussionmentioning

confidence: 84%

Quantitative ontogeny of murine insulin-like growth factor (IGF)-I, IGF-binding protein-3 and the IGF-related acid-labile subunit

Hwang

Lee

Cohen

2008

Growth Hormone & IGF Research

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We report the first ontological studies of IGF-I, IGFBP-3 and ALS in mice using newly-characterized sensitive, homologous immunoassays. Our results indicate that mice have a generally similar pattern in IGF-related axis components, with low levels early in life, increasing to peak during sexual maturation and declining thereafter. Significant gender differences in non-pregnant levels and dramatic changes during pregnancy were also found. Knowledge of the normal developmental changes in the murine IGF system and accurate tools for investigations of this system are a necessary foundation for research in this field.

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“…Transgenic mice overexpressing GH show increased body weight, organomegaly -particularly in the liver -increased circulating IGF-I and hepatic IGF-I mRNA levels, among other alterations (Table 2; Mathews et al 1988, McGrane et al 1990, Sotelo et al 1998, Hoeflich et al 2001, Bartke 2003, Iida et al 2004. The disproportional increase in liver weight is due to hypertrophy and hyperplasia (Orian et al 1989, Hoeflich et al 2001, Snibson 2002, Bartke 2003, most likely as a consequence of a direct action of GH on hepatocytes rather than effects mediated by IGF-I (Quaife et al 1989, Bartke 2003.…”

Section: Discussionmentioning

confidence: 99%

Transgenic mice overexpressing GH exhibit hepatic upregulation of GH-signaling mediators involved in cell proliferation

Miquet¹,

González²,

Matos³

et al. 2008

Journal of Endocrinology

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Chronically elevated levels of GH in GH-transgenic mice result in accelerated growth and increased adult body weight. We have previously described that the GH-induced JAK2/STAT5-signaling pathway is desensitized in the liver of transgenic mice overexpressing GH. However, these animals present increased circulating IGF-I levels, increased hepatic GHR expression, and liver organomegaly due to hypertrophy and hyperplasia, which frequently progress to hepatomas as the animals age, indicating that action of GH on the liver is not prevented. In the present study, we have evaluated other GH-signaling pathways that could be activated in the liver of GH-transgenic mice. Upon GH administration, normal mice showed an important increment in STAT3 phosphorylation level, but transgenic mice did not respond to acute GH stimulation. However, STAT3 was constitutively phosphorylated in transgenic mice, whereas its protein content was not increased. GH-transgenic mice showed overexpression of c-Src, accompanied by an elevation of its activity. Other signaling mediators including focal adhesion kinase, epidermal growth factor receptor, Erk, Akt, and mammalian target of rapamycin displayed elevated protein and basal phosphorylation levels in these animals. Thus, GH-overexpressing transgenic mice exhibit hepatic upregulation of signaling mediators related to cell proliferation, survival, and migration. The upregulation of these proteins may represent GH-signaling pathways that are constitutively activated in the presence of dramatically elevated GH levels throughout life. These molecular alterations could be implicated in the pathological alterations observed in the liver of GH-transgenic mice.

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Growth hormone (GH) receptors, binding proteins and IGF-I concentrations in the serum of transgenic mice expressing bovine GH agonist or antagonist

Cited by 24 publications

References 23 publications

Dose-response effects of a new growth hormone receptor antagonist (B2036-PEG) on circulating, hepatic and renal expression of the growth hormone/insulin-like growth factor system in adult mice

Dose-response effects of a new growth hormone receptor antagonist (B2036-PEG) on circulating, hepatic and renal expression of the growth hormone/insulin-like growth factor system in adult mice

Quantitative ontogeny of murine insulin-like growth factor (IGF)-I, IGF-binding protein-3 and the IGF-related acid-labile subunit

Transgenic mice overexpressing GH exhibit hepatic upregulation of GH-signaling mediators involved in cell proliferation

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