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Endocrinology Vol. 145, No. 4 1564-1570
Copyright © 2004 by The Endocrine Society

Tissue-Specific Regulation of Growth Hormone (GH) Receptor and Insulin-Like Growth Factor-I Gene Expression in the Pituitary and Liver of GH-Deficient (lit/lit) Mice and Transgenic Mice that Overexpress Bovine GH (bGH) or a bGH Antagonist

Keiji Iida, Juan P. Del Rincon, Dong-Sun Kim, Emina Itoh, Ralf Nass, Karen T. Coschigano, John J. Kopchick and Michael O. Thorner

Division of Endocrinology and Metabolism (K.I., J.P.R., D.-S.K., E.I., R.N., M.O.T.), Department of Internal Medicine, University of Virginia, Charlottesville, Virginia 22908; and Edison Biotechnology Institute (K.T.C., J.J.K.) and Department of Biomedical Sciences (J.J.K.), College of Osteopathic Medicine, Ohio University, Athens, Ohio 45701

Address all correspondence and requests for reprints to: M. O. Thorner, Box 800466, Department of Internal Medicine, University of Virginia, Charlottesville, Virginia 22908. E-mail: mot{at}virginia.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
GH has diverse biological actions that are mediated by binding to a specific, high-affinity cell surface receptor (GHR). Expression of GHR is tissue specific and a requirement for cellular responsiveness to GH. IGF-I is produced in multiple tissues and regulated in part by GH through GHR. In this study, we evaluated GHR and IGF-I mRNA expression in pituitary gland and compared the levels with those derived from liver of bovine GH transgenic, GH antagonist transgenic, lit/lit mice, and their respective controls using real-time RT-PCR. In liver, both GHR and IGF-I mRNA expressions were regulated in parallel with GH action in all three animal models, and there was a strong correlation between GHR and IGF-I mRNA levels. In the pituitary gland, increased expression of IGF-I mRNA in the pituitary of bovine GH transgenic mice was observed, whereas IGF-I expression in GH antagonist transgenic or lit/lit mice was similar to that observed in control animals. There were no differences of GHR mRNA levels in pituitary gland of any groups we examined. There was also no correlation between GHR and IGF-I mRNA levels in any group in the pituitary gland. In conclusion, we found that hepatic GHR and IGF-I mRNA levels were strongly correlated with each other in chronic GH excess or deficient state, and that regulation and correlation between local GHR and IGF-I mRNA levels induced by GH is different between liver and pituitary gland.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
GH HAS DIVERSE biological actions that are mediated by binding to a specific, high-affinity cell surface receptor (GHR) (1). Expression of this receptor is a requirement for cellular responsiveness to GH. Tissue sensitivity to GH depends, at least in part, upon the abundance of GHR (2). GH does not only stimulate IGF-I production but also can regulate GHR expression. GHR mRNA expression in GH-deficient rodents has been found to be down-regulated in white adipose tissue (3, 4), unchanged in brain, spleen, kidney, heart, and skeletal muscle (5, 6), and either down-regulated, up-regulated, or unchanged in liver (2, 4, 5, 6, 7, 8).

The pituitary gland is normally exposed to high local concentrations of GH. It is thus likely that a mechanism or mechanisms to decrease responsiveness to GH in the pituitary gland is present. One such mechanism might be a decreased level of GHR. The regulation of GHR by GH in pituitary gland, to the best of our knowledge, has not been reported before.

There are some reports supporting that pituitary IGF-I expression is also regulated by GH (9, 10). The IGF-I mRNA expression of GH3 cells and primary rat anterior pituitary cells was markedly diminished when these cells were grown in T3-depleted medium that decreases GH synthesis (9). Addition of T3 or GH induced IGF-I mRNA transcripts and protein in a time- and dose-dependent manner (9). In vivo, administration of T3 or GH to thyroidectomized rats enhanced expression of pituitary IGF-I (10), and IGF-I expression was increased in rats harboring somatomammotrope tumors that had high circulating GH concentrations (11).

If both IGF-I and GHR are regulated by GH action in a specific tissue, a correlation is likely to be found. We therefore studied in vivo: 1) the absolute GHR mRNA level in pituitary gland and compared it to that in liver; 2) the regulation of GHR by GH in mouse models with either increased, moderately decreased, and severely decreased GH action; and 3) the relationship between GHR and IGF-I mRNA levels in liver and pituitary gland.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals and tissues
All studies were performed in 3-month-old male mice. Three different strains of mice, referred to as bGH (giant transgenic mice that overexpress bovine GH) (12), GHA (dwarf mice that overexpress bovine GH-G119K antagonist) (12, 13), and lit/lit (dwarf mice with an inactivating mutation of GHRH receptor) (14) were used in this study. Their respective nontransgenic littermates or lit/+ for lit/lit mice were used as controls. The production and characterization of transgenic mice expressing either bGH or GH-G119K (GHA) genes have been described in detail (12, 13). Expression of a transgene encoding either bGH or GHA was directed by mouse metallothionein I (MT) transcriptional regulatory region. Food and water were supplied ad libitum. The previously published serum IGF-I concentrations for bGH, GHA, and lit/lit mice are approximately 200%, 40%, and 20% of normal, respectively (12, 15, 16). Pituitary glands and livers from the mice (n = 5/group) were collected and flash-frozen in liquid nitrogen and then stored at -80 C for subsequent mRNA analysis. All animal protocols were approved by the University of Virginia’s and the Ohio University’s Institutional Animal Care and Use Committees.

Total RNA preparations
The RNA extraction was performed using TRI Reagent (Molecular Research Center, Inc., Cincinnati, OH) followed by RNeasy Mini Kit (QIAGEN, Valencia, CA) according to the manufacturer’s instructions. To eliminate genomic deoxy-RNA (DNA) from the samples, deoxyribonuclease I treatment (QIAGEN) was included in the RNA isolation procedure. The quantity of extracted total RNA was determined using the RiboGreen RNA Quantitation Kit (Molecular Probes, Eugene, OR) with a Genios multidetection plate reader (Phenix Research Product, Hayward, CA).

Primer design
All primers were purchased from QIAGEN. Primers for murine GH, GHR, and IGF-I were designed to produce amplification products which spanned at least two exons of the protein coding sequence to avoid amplification of genomic DNA. 18S rRNA was used as an internal control and was amplified with previously reported primers (17). Primer sequences and the expected size of real-time RT-PCR products are listed in Table 1Go. We also designed primers specific for bGH to confirm that primers specific for murine and bovine GH did not cross-react. The primer pairs we used to amplify GHR coded exclusively for GHR and not for GHBP because they were directed to the intracellular domain of GHR.


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  		TABLE 1. Forward (-F) and reverse (-R) primer sequences, amplification product length, and concentration used to measure gene expressions by real-time RT-PCR

 
RT
One microgram total RNA from the liver and 100 ng total RNA from the pituitary were reverse-transcribed in a total volume of 10 µl using the iScript cDNA Synthesis Kit (Bio-Rad Laboratories, Hercules, CA). Reactions were incubated for 5 min at 25 C, 30 min at 42 C, and 5 min at 85 C. Reaction lacking reverse transcriptase were also performed to generate controls for assessment of genomic DNA contamination. A 1:20 dilution of the resultant cDNA was prepared, and 4 µl of this template was used in the real-time PCR protocol.

Plasmid construction
A PCR fragment generated using primers listed in Table 1Go was cloned in the pGEM-T vector (Promega, Madison, WI) and introduced in Esherichia coli JM109 (Promega). From a selected transformant containing the desired construct, plasmid DNA was isolated using the Qiaprep Spin Miniprep Kit (QIAGEN). The DNA concentration of each resulting plasmid was measured using a Biomate spectrophotometer (260 nm/280 nm) (Thermo Spectronic, Rochester, NY). A serial dilution of each plasmid was used to make a standard curve for quantification.

PCR
The iCycler iQ Real-Time PCR detection system (Bio-Rad Laboratories, Inc.) was used for sample cDNA quantification. Each reaction contained cDNA, 200 µmol/liter each deoxyribonucleotide triphosphate, forward and reverse primers, the concentrations of which are listed in Table 1Go, 2 mmol/liter MgCl2, 0.5 IU Jumpstar Taq DNA polymerase (Sigma, St. Louis, MO) with supplied buffer, and 10 nM fluoresceine calibration dye (Bio-Rad Laboratories, Inc.). In addition, SYBR Green I (1:75,000 of 10,000x stock solution) (Molecular Probes) was added and made up to a total volume of 20 µl with sterile water. The real-time PCR protocol was 5 min at 95 C followed by 40 cycles of 15 sec at 94 C, 40 sec at 62 C, and 45 sec at 72 C. To assess PCR specificity, melting curves from 55–95 C in 0.5 C steps of 10 sec each were generated. PCR products of each assay were also subjected to agarose gel electrophoresis to further confirm amplification specificity. PCR efficiencies of all reactions were between 95% and 100%. All measurements were performed in triplicate and repeated a series of experiments twice independently except for the RNA extraction step. All specific quantities were corrected for the amount of 18S rRNA amplified.

Quantification
A standard curve was generated by amplifying serial dilutions of a known quantity of plasmid. The standards in triplicate and cDNA samples were then coamplified in the same reaction. The standard curve displayed a linear relationship between cycle threshold values and the logarithm of input plasmid copy number. The dynamic range of the standard curve spanned at least five orders of magnitude. The amount of product in a particular sample is determined by interpolation from a standard curve of cycle threshold values generated from the plasmid dilution series.

Statistical analysis
Results are expressed as mean ± SEM. Differences were determined by unpaired t test. Coefficients of linear correlation (Pearson’s) for GHR and IGF-I mRNA levels were calculated using Prism 3.0 software. P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Weights of mice are shown in Table 2Go. PCR specificity was confirmed using melting curves and agarose gel electrophoresis. Agarose gel electrophoresis demonstrated a single band with the expected size, and all products showed a single melting peak on real-time PCR (data not shown). The primer pairs used to amplify murine GH did not cross-react with bovine GH (Fig. 1AGo, lane 7). The pituitaries of GHA and bGH transgenic mice expressed bovine GH as well as murine GH (Fig. 1AGo, lanes 3–6), showing that the transgene driven by MT promoter (MT-bGH) was expressed in the pituitary gland. Figure 1BGo shows the expression of MT-bGH (G119K) or MT-bGH in liver of GHA and bGH mice, respectively, but not in that of littermate controls.


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  		TABLE 2. Weights of animals

 


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  		FIG. 1. A, Agarose gel electrophoresis of RT-PCR products derived from the pituitary of wild-type mice (wild), GHA, bGH, or bovine pituitary RNA with specific primers for murine (m) or bGH. Because RT-PCR was performed with 40 cycles of amplification, the results were qualitative but not quantitative. B, Agarose gel electrophoresis of RT-PCR products derived from the liver of wild, GHA, and bGH mice with primer pair specific for bGH (b).

 
Hepatic IGF-I mRNA levels of bGH mice were 315% of those of controls. Those of GHA or lit/lit mice were 37% and 12% of those of control or lit/+ mice, respectively (Fig. 2Go). Hepatic GHR mRNA levels of bGH mice were 507% of those of control mice. Those of GHA or lit/lit mice were 34% and 51% of those of control or lit/+ mice, respectively (Fig. 3Go).



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  		FIG. 2. IGF-I mRNA levels in liver. n = 5/each group. **, P < 0.01 vs. respective control mice.

 


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  		FIG. 3. GHR mRNA levels in liver. n = 5/each group. *, P < 0.05; **, P < 0.01 vs. respective control mice.

 
In the pituitary gland, murine GH mRNA levels of bGH mice were markedly suppressed (14% of control). Those of GHA mice were increased (273% vs. control) and of lit/lit mice were suppressed (22% of those in lit/+ mice) (Fig. 4Go). Pituitary IGF-I mRNA levels of bGH mice were significantly increased (207%) compared with those of control mice. On the other hand, those of GHA or lit/lit mice were comparable to those of control or lit/+ mice, respectively (Fig. 5Go). Pituitary GHR mRNA levels of bGH, GHA, or lit/lit mice were extremely low and comparable with those of each control mice (Fig. 6Go).



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  		FIG. 4. Murine GH mRNA levels in pituitary gland. n = 5/each group. *, P < 0.05 vs. control mice; **, P < 0.01 vs. respective control mice.

 


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  		FIG. 5. IGF-I mRNA levels in pituitary gland. n = 5/each group. *, P < 0.05 vs. respective control mice. NS, Not significant.

 


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  		FIG. 6. GHR mRNA levels in pituitary gland. n = 5/each group. NS, Not significant.

 
We also quantitated the MT-bGH or MT-bGH (G119K) mRNA levels in liver as well as in pituitary. In bGH mice, the expressions of MT-bGH /18S rRNA in liver and in pituitary gland were 0.044 ± 0.005 (copy number) and 0.0031 ± 0.0003 (copy number), respectively. In GHA mice, the expressions of MT-bGH (G119K)/18S rRNA in liver and in pituitary gland were 0.032 ± 0.007 (copy number) and 0.0020 ± 0.0005 (copy number), respectively. The relative amount of murine GH and MT-bGH in pituitary gland was summarized in Table 3Go.


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  		TABLE 3. Comparison of the local expression between murine GH and MT-bGH in pituitary gland

 
Because the mRNA changes of IGF-I and GHR appeared to correlate with GH action in the liver, we examined the correlation between IGF-I and GHR mRNA in liver and pituitary gland. Despite the small size of the groups, there were significant linear correlations between IGF-I and GHR mRNA levels in liver of the lit/lit and GHA mice, and there was a trend toward correlation in the control group for GHA (r = 0.823, P = 0.087), and in the control group for bGH (r = 0.870, P = 0.055). In bGH group, the GHR expression was high, and this was associated with high IGF-I mRNA (Fig. 7Go). In contrast, there was no significant correlation in any group between the same variables in the pituitary gland (Fig. 8Go).



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  		FIG. 7. There was a correlation between IGF-I and GHR mRNA levels in a group of lit/lit, or GHA mice (lit/lit: r = 0.970, P = 0.006; GHA: r = 0.987, P = 0.002), and there was a trend toward correlation in the control group for GHA (r = 0.823, P = 0.087), and in the control group for bGH (r = 0.870, P = 0.055). There was also a significant linear correlation between GHR and IGF-I mRNA levels in liver if all groups are analyzed together (r = 0.912, P < 0.0001).

 


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  		FIG. 8. No correlation was observed between IGF-I and GHR mRNA levels in any group in pituitary gland.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study, we used three mouse models with different levels of GH action. We have investigated the regulation of IGF-I and GHR mRNAs in pituitary gland of these mice and compared these results with those in liver. Interestingly, we found that there was a strong correlation in the mRNA levels between IGF-I and GHR in liver, but not in pituitary. In addition, we believe this is the first report concerning the regulation of GHR mRNA by GH in pituitary gland.

GH enhances IGF-I transcription (18) and increases IGF-I mRNA abundance in most tissues (19). In liver, our results confirmed increased levels of IGF-I mRNA in bGH mice and decreased levels in GHA and lit/lit mice, which are consistent with circulating IGF-I levels. There are conflicting results concerning the regulation of hepatic GHR by GH (2). Chronic GH therapy to a normal, wild-type animal increases GH binding in hepatic tissue (20, 21, 22). On the other hand, a single GH injection to GH-deficient mice resulted in down-regulation of GH binding to hepatic GHR (23), suggesting that the effect of GH on hepatic GHR expression might depend on the duration of exposure to GH. Alternatively, it might depend on the concentration of circulating GH or pulsatility. Hepatic GHR increased more in response to continuous than to pulsatile administration of GH (24, 25). Our data in bGH mice demonstrated that hepatic GHR mRNA levels were markedly increased compared with those of control mice. The chronic exposure to high GH levels and/or the nonpulsatile pattern of exposure might enhance the up-regulation of hepatic GHR. Alternatively, insulin might play a role in the up-regulation of hepatic GHR because bGH mice are known to have elevated insulin concentrations (26). In this report, hepatic GHR mRNA levels in GHA or lit/lit mice were decreased, in parallel with GH action. In GHA mice, Chen et al. (12) reported that the binding properties of GH to the hepatic membranes increased. On the other hand, Sotelo et al. (27) showed that hepatic uptake of injected labeled bGH in GHA mice was reduced to 1/5 of the values measured in normal animals. Taken together with our results, hepatic GHR mRNA levels in GHA mice parallel GH action; GHR protein levels on the cell surface do not change in parallel because recruitment of hepatic GHR might be impaired because the GH antagonist inhibits proper GHR dimerization and degradation in this model. Interestingly, we observed a strong correlation between hepatic IGF-I and GHR mRNA levels in groups with normal, partially reduced (GHA) and severely reduced (lit/lit) GH action. It was not surprising that there was no correlation in bGH group because the GHR and IGF-mRNA levels were already high. Furthermore, GHR/IGF-I ratio appeared to decrease in parallel with GH action (Fig. 7Go). These results suggest that a common factor or factors, including GH per se, may regulate both IGF-I and GHR mRNA levels in liver.

In the pituitary gland, our results showed that murine GH mRNA levels in bGH mice were extremely reduced. This decrease of murine GH expression can be explained by the effect of negative feedback of increased circulating IGF-I concentration at the pituitary and/or by feedback by circulating GH at the hypothalamus (28). Stefaneanu et al. (29) found that GH-immunoreactive cells were markedly reduced in size and moderately decreased in number in a bGH mouse model, suggesting that reduced GH mRNA is accompanied by hypoplasia of somatotropes. On the other hand, our results showed that murine GH mRNA levels in GHA mice were significantly increased compared with control littermates. The increase of murine GH could be explained by reduced negative feedback of low concentration of circulating IGF-I and is in agreement with a previous report describing protein levels of GH in these mice (12). The local expression of MT-bGH or MT-bGH (G119K) in pituitary gland should also be taken into account in bGH or GHA mice. However, the expression of MT-bGH or MT-bGH (G119K) in pituitary was small compared with murine GH (Table 3Go). As expected, our results showed that expression of GH in lit/lit mice was reduced compared with lit/+ mice. Lin et al. (30) found that somatotropes of lit/lit mice were reduced in size and number, also suggesting that reduced GH mRNA is accompanied by hypoplasia of somatotropes in this model. Taken together with the results from bGH mice, diminished GHRH receptor signaling seems to be responsible for both reduced murine GH mRNA expression and hypoplasia of somatotropes.

We showed that the expression of IGF-I in pituitary of GHA was comparable to those of control littermates despite low GH action and low concentrations of circulating IGF-I. It should be noted that murine GH mRNA levels were increased (Fig. 4Go) and locally produced MT-bGH (G119K) was negligible in pituitary gland (Table 3Go). Unexpectedly, pituitaries of lit/lit mice and lit/+ mice also showed comparable levels of IGF-I mRNA in pituitary gland despite reduced expression of local GH as well as circulating GH in lit/litmice. One possible explanation is that GH-independent factors may maintain local production of IGF-I in chronic state of reduced GH action such as lit/lit or GHA mice. It is interesting that pituitaries of other animal models with low circulating IGF-I levels induced by streptozotocin (31) or food-deprived (32) also demonstrated no changes of IGF-I mRNA in pituitary gland. In contrast, we showed that IGF-I mRNA levels in pituitary of bGH mice were increased significantly, suggesting that excessive GH played an additive role to stimulate IGF-I expression in pituitary gland. Our results also confirmed the previous report demonstrating that GH stimulates the IGF-I expression in pituitary gland in an endocrine rather than autocrine/paracrine fashion (11). Fagin et al. (11) evaluated pituitary IGF-I gene expression in rats harboring sc implanted somatomammotropic tumors. The pituitary IGF-I gene expression was stimulated in these animals despite reduced pituitary GH mRNA expression. Therefore, they concluded that stimulated pituitary IGF-I mRNA appeared to be dependent on endocrine, and not paracrine, pituitary GH concentrations. Our results using bGH mice also demonstrated that pituitary IGF-I mRNA levels in bGH mice were approximately twice as high as those in control mice, whereas pituitary GH mRNA levels in bGH mice were 14% of those in control mice.

In contrast to the results from liver, GHR mRNA levels in pituitary were not statistically different in all three animal models we used. In addition, we confirmed that GHR mRNA levels in pituitary were extremely low compared with 18S rRNA (Fig. 6Go). Low levels of GHR mRNA may be responsible for reduced GH responsiveness, and for unaltered IGF-I mRNA levels in pituitary of all mice we used except of bGH mice. Moreover, our results showed that there was no correlation between IGF-I and GHR mRNA levels in pituitary gland in any mice group (Fig. 8Go), in contrast with the results from liver (Fig. 7Go). The physiological significance of GHR in pituitary is still unclear. The pituitary cells of GHR-disrupted mice exhibited normal ultrastructural morphology except for hyperplasia of somatotropes (33). However, Honda et al. (34) detected the GHR mRNA using in situ hybridization technique on somatotropes, lactotropes, and some gonadotropes, but not corticotropes or thyrotropes in mice. Moreover, they demonstrated that GH stimulated IGF-I mRNA expression directly in cultured mouse anterior pituitary cells, suggesting that GHR mRNA detected in pituitary cells was translated into the functional protein. The localizations of GHR in pituitary gland suggest that GHR might play a role in the cell biology of somatotropes, lactotropes, and/or gonadotropes although disrupted GHR signaling causes no morphological changes on these cells (33).

There are several distinct 5' untranslated region variants in mouse GHR (35, 36). Expression of each transcript is regulated in a tissue- and developmental stage-specific manner. The difference of regulation of GHR expression between liver and pituitary may be explained by use of different transcripts. Further investigation is required to clarify the regulation of GHR in pituitary gland.

In conclusion, our results showed that regulation of GHR as well as IGF-I mRNA levels are tissue specific. There was a significant correlation in the mRNA levels between hepatic GHR and IGF-I. The local expression of GHR may play a role to regulate GHR signaling in a tissue-specific manner to maintain the local homeostasis.


   Acknowledgments
 
We are grateful to Dr. Bruce Gaylinn, Amy Holland, and Pattie Hellmann for their excellent technical assistance.


   Footnotes
 
This work was supported in part by a grant from Foundation for Growth Science in Japan (to K.I.) and by a grant from Pharmacia Corp (to M.O.T.) and a gift to the laboratory by Mr. and Mrs. Sal Ranieri. J.J.K. is supported, in part, by the state of Ohio’s Eminent Scholar Program that includes a gift by Milton and Lawrence Goll and by DiAthegen, LLC.

Abbreviations: bGH, Bovine transgenic GH; GHA, GH antagonist transgenic; GHR, GH receptor; MT, metallothionein I.

Received November 3, 2003.

Accepted for publication January 7, 2004.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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