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Does Serum Growth Hormone (GH) Binding Protein Reflect Human GH Receptor Function?

Department of Pharmacology, Bruce Rappaport Faculty of Medicine, Technion, and Rambam Medical Center, Haifa 31096, Israel

Address correspondence and requests for reprints to: Dr. Ze’ev Hochberg, Rambam Medical Center, POB 9602, Haifa 31096, Israel. E-mail: Z.HOCHBERG{at}RAMBAM.HEALTH.GOV.IL

	Abstract

Top Abstract Introduction Species divergence Tissue divergence GHR turnover GHBP-generating protease hGHR mRNA splicing GHBP-positive GHIS Summary Clinical implications References

 
Previous observations raised the possibility that circulating GH-binding protein (GHBP) may serve as a useful index for tissue GH receptor (GHR) responsiveness in humans. Indeed, there are many examples to indicate that across a wide scope of comparative studies, ontogenic data, experimental systems, physiological conditions, nutritional states, and diseases there is a close relationship between the concentration of GHR and the level of serum GHBP. In the present review, we discuss various aspects that might affect differentially cellular GHR and circulating GHBP, based on species and tissue divergence, regulation of cell-surface GHR turnover, GHR cleavage mechanism, GHR mRNA splicing, and GH insensitivity (GHI) syndrome patients with normal or high serum GHBP levels. Most previous experimental data were collected through comparative analysis of human GHBP against GHR and GHBP determinations in animal models. Yet, GHBPs possess species-specific properties, and the mechanism for their generation and regulation display evolutionary divergence. Another important aspect is tissue divergence, in terms of GHR regulation and its cleavage to GHBP. Although GHBP is generated mainly from the liver GHR, many other tissues express GHRs and probably also contribute to the total GHBP level. Human GHBP is generated by proteolytic cleavage of GHR at the cell-surface and, thus, occupancy or modulation of GHR turnover/internalization would impact the level of cell-surface GHR that are available for proteolysis. An additional degree of complexity arises from recent reports, implicating a protein kinase C-regulated metalloprotease activity in GHBP generation. This suggests that the proteolytic system, which controls the specific cleavage mechanism and switch between GHR proteolysis and GHBP shedding, is a regulated process. Finally, differential splicing regulation to the full-length, active human GHR (hGHR) and the inactive truncated hGHRtr isoform messenger RNA transcripts might regulate both the production of GHBP and GHR bioactivity, as hGHRtr generates large amounts of GHBP but has a dominant negative effect on GH signaling. Several clinical GH-resistant conditions, such as liver cirrhosis, renal insufficiency, insulin-dependent diabetes mellitus, hypothyroidism, malnutrition, or critical illness are associated with reduced GHBP levels. However, this is not universally true, as in other conditions (e.g. early childhood, acromegaly) decreased GHBP levels are not associated with GHI. Divergence between serum GHBP and insulin-like growth factor I, such as which occur during puberty or obesity, also questions whether GHBP levels reflect GHR function. Even in patients with GHI syndrome, serum GHBP cannot be relied on to detect all GHR mutations.

The correct assessment of GHR expression and GH functionality in an individual patient will require, in parallel to measurements of serum GHBP, additional detailed diagnostic screening of the entire GH-insulin-like growth factor I axis.

	Introduction

Top Abstract Introduction Species divergence Tissue divergence GHR turnover GHBP-generating protease hGHR mRNA splicing GHBP-positive GHIS Summary Clinical implications References

 
FOURTEEN years have elapsed since the identification of serum GH-binding protein (GHBP) (1, 2), which corresponds to the extracellular domain of the GH receptor (GHR) (3). Under normal physiological conditions, GHBP is complexed with about half of the GH in human plasma (4, 5) and acts as a reservoir or a buffer, damping the oscillations of plasma GH, prolonging GH half-life, and modulating GH bioactivity through competition with GHR for GH (6, 7). Previous observations raised the possibility that circulating GHBP may serve as useful index of tissue GHR responsiveness in humans, in whom direct receptor measurements are difficult because of accessibility and ethical considerations. It was felt that a new horizon was opened, in that clinicians would now have an access to measure tissue GHR status by measuring serum GHBP in a blood sample. Indeed, there are many examples to indicate that across a wide scope of comparative studies, ontogenic data, experimental systems, physiological conditions, nutritional states, and diseases there is a close relationship between the concentration of GHR and the level of serum GHBP (for review, see Refs. 7, 8, 9, 10). In addition, it was previously shown that both cell-membrane GHR and serum level of GHBP are negatively correlated with GH pulsatility in a variety of physiological and pathological conditions (9, 11). In some of these conditions, serum insulin-like growth factor I (IGF-I) is low and thereby might contribute to increased GH levels through diminished negative feedback.

It was then attempted to screen for GH insensitivity syndrome (GHIS) by measuring circulating GHBP (12, 13, 14, 15). When GHBP measurements were performed in patients with complete GHIS, it was found that in the great majority of cases serum GHBP was either absent or markedly reduced (for review, see Refs. 16, 17, 18), and among GH-deficient children GHBP was shown to correlate with the response to GH therapy (19). Yet, several GHIS patients had normal or even elevated levels of serum GHBP (16, 17, 18).

However, in light of the progress in GHBP research, relating to the mechanism of GHBP generation and the complex interrelationship between soluble GHBP and cellular GHR, it is pertinent to reexamine the question whether the circulating GHBP is a reliable marker of GHR functionality. In the present review, we discuss various aspects that might affect differentially GHR and GHBP, based on species and tissue divergence, regulation of cell-surface GHR turnover, GHR cleavage mechanism or GHR messenger RNA (mRNA) splicing, and GHIS patients with normal or high serum GHBP levels.

	Species divergence

Top Abstract Introduction Species divergence Tissue divergence GHR turnover GHBP-generating protease hGHR mRNA splicing GHBP-positive GHIS Summary Clinical implications References

 
A direct measurement of GHR in human is difficult, due to obvious ethical and practical limitations. Thus, implications regarding the regulation of circulating human GHBP can at best be extrapolated from animal studies. However, substantial differences occur among GHBP of various mammalian sera, which were previously classified into four main groups, according to their binding activity and hormonal specificity (20): 1) rat and mouse (20, 21, 22, 23, 24, 25, 26); 2) ox, sheep, and goat (20, 27, 28, 29); 3) rabbit, horse, pig, dog, and cat (20, 30); and 4) human and monkey (1, 2, 20, 31). This classification of serum GHBP was strengthened by Wallis (32), who identified mammalian species on the basis of the rates of GH evolution.

Another important divergence derives from the difference in the mechanism of GHBP generation among various species. In rodents, the soluble GHBP is, at least partly, generated from an alternatively spliced mRNA of GHR (22, 23, 33), whereas in humans and rabbits GHBP is generated by proteolytic cleavage of the ectodomain of the membrane-bound GHR (3, 34, 35). This different mechanism of GHBP origin could have important implications for the regulation of GHBP generation: for mRNA splicing, GHBP can be produced as an independent secretory product; in the case of proteolytically derived GHBP, GHR is an obligatory intermediate. In addition, the protease involved in GHBP cleavage could be regulated quite separately. Indeed, serum GHBP is variously regulated in different species, such as with regard to sexual dimorphism or pregnancy (36, 37).

In addition, in human, rabbit, rat, and mouse an alternative splicing in the cytoplasmic domain results in a truncated isoform (GHRtr) that was demonstrated in humans to produce large amounts of GHBP through proteolysis (35, 38, 39). However, Dastot et al. (40) described recently an evolutionary divergence in the ability of this new transmembrane isoform, GHRtr, to generate GHBP: large amounts of GHBP were secreted by COS-7 cells expressing human or rabbit GHRtr, whereas, in contrast, no GHBP was detected in cells expressing rat GHRtr. Thus, experimental animal models in studies of GHBP must be cautiously interpreted. Experimental data suggest that the rabbit seems to be the most suited animal model for human GHR/GHBP studies (20, 40).

	Tissue divergence

Top Abstract Introduction Species divergence Tissue divergence GHR turnover GHBP-generating protease hGHR mRNA splicing GHBP-positive GHIS Summary Clinical implications References

 
GHRs are most abundant in the liver (41, 42, 43), and, thus, this tissue is likely to be the major source of serum GHBP. Indeed, low serum GHBP levels were observed in human patients with liver cirrhosis (44, 45, 46) and after partial hepatectomy in the rat (47).

However, GHRs are widely expressed in other human tissues, including adipose tissue, muscle, kidney, heart, brain, and so on (42, 43, 48, 49), that probably also contribute to the total level of circulating GHBP, although it is unknown whether cleavage occurs to the same degree in each tissue.

An additional consideration is that the regulation of GHR might vary, depending on the target organ considered, as was previously demonstrated in ontogenic, nutritional, and hormonal regulation studies (50). Furthermore, in in vitro studies, dexamethasone was shown to decrease GHR in 3T3-F442A fibroblasts (51) but to increase GHR in cultured rat hepatocytes (52, 53) and in the osteosarcoma cell-line UMR-106.01 (54). Tissue-specific regulation may also clarify the possible divergence between the negative correlation shown for GHR expression on peripheral blood lymphocytes vs. body mass index (55) and the positive linear correlation of serum GHBP vs. body mass index (56, 57, 58, 59, 60, 61, 62). Because GHBP was shown to correlate positively with adiposity variables, it is suggested that the adipose tissue may be an important source of GHBP (61, 62).

Furthermore, the full-length human GHR (hGHR) and the recently described exon 9 spliced variant hGHRtr, the nature of which is described later, have different expression patterns in various human tissues, with the hGHR being the most abundant isoform (35, 63). We have recently measured the relative expression of the two splice isoforms in rhesus monkeys and found that whereas the liver, muscle and adipose tissues expressed about 5% GHRtr mRNA of the GHR transcript, the hypothalamus, pituitary, renal cortex, and lung expressed only minor amounts of this isoform (unpublished observation). Since hGHRtr was demonstrated to generate larger amounts of GHBP than hGHR (35, 38, 39), the divergence in the relative expression of hGHR isoforms would presumably affect the level of GHBP that each tissue generates.

	GHR turnover

Top Abstract Introduction Species divergence Tissue divergence GHR turnover GHBP-generating protease hGHR mRNA splicing GHBP-positive GHIS Summary Clinical implications References

 
The occupancy and membrane traffic of the GHR seem to be important factors in modulating GHBP generation. To understand the complex interrelationship between GHR internalization and GHBP shedding, the following sequence of events is proposed: 1) on GH binding to cell-surface GHR, a single molecule of GH is bound sequentially by a dimer of GHR, leading to signal transduction; 2) GHR is internalized via clathrin-coated pits, and the internalization is dependent on an intact unbiquitination system and an intact endocytic pathway. Internalization/down-regulation is independent of Jak-Stat signal transduction (64, 65); 3) ligand-induced internalization is followed by degradation of most of the GH-GHR complex, whereas a small fraction is recycled to the membrane (for review, see Refs. 66, 67, 68, 69); and 4) monomeric GHRs, either occupied or unoccupied by GH, undergo proteolytic cleavage to generate GHBP (Fig. 1). Because the occupancy of the full-length GHR seems to be an important factor in modulating the turnover rate of the receptor (66, 70), regulation of GHR turnover would be expected to modulate the level of GHR at the cell-surface that is available for proteolytic cleavage.

View larger version (31K): [in this window] [in a new window]   Figure 1. Schematic representation of the regulation of GHBP generation on GH (1 ) binding to cell-surface GHR, a single molecule of GH is sequentially dimerized by two GHR molecules (2 ), leading to signal transduction (3 ). GHR is internalized (4 ) via clathrin-coated pits. In addition to the full-length GHR (6 ), a short isoform, GHRtr (7 ), is produced by splicing (5 ) of an alternative 3' acceptor splice site, 26 bp downstream in exon 9. After cell activation by PKC, a GHBP-generating protease (8 ) and GHR and/or GHRtr become coclustered and can interact to generate GHBP. When compared with GHR, GHRtr generates large amounts of GHBP (thick arrow).

	GHBP-generating protease

Top Abstract Introduction Species divergence Tissue divergence GHR turnover GHBP-generating protease hGHR mRNA splicing GHBP-positive GHIS Summary Clinical implications References

	hGHR mRNA splicing

Top Abstract Introduction Species divergence Tissue divergence GHR turnover GHBP-generating protease hGHR mRNA splicing GHBP-positive GHIS Summary Clinical implications References

 
Truncated forms of hGHRtr that lack most of the intracellular domain of hGHR, were described (35, 38); the nucleotide sequence of hGHRtr mRNA species was identical to that of hGHR, except for a 26-bp deletion, leading to a stop codon at position 280, resulting in the truncation of 97.5% of the cytoplasmic domain (Fig. 1). In human tissues, the hGHRtr is expressed at a low level, compared with the full-length receptor (35, 38, 63). Functional studies confirmed that although hGHRtr is inactive by itself, it could act as a dominant-negative regulator of the full-length hGHR (38). hGHRtr fails to internalize/down-regulate, being relatively fixed at the cell membrane (39, 65) and when compared with hGHR, hGHRtr shows a significantly increased capacity to generate GHBP (35, 38, 39, 40), suggesting that it may provide a mechanism for the production of GHBP. These findings suggest that differential expression of GHR isoforms could play a significant role in GHR signaling, GHR cleavage, and GHBP generation.

Indeed, mutations that lead to increased level of hGHRtr at the cell surface fail to internalize, heterodimerize with the full-length hGHR, inhibit signaling, and generate high levels of GHBP (86, 87).

Recently, the expression of hGHR and hGHRtr has been studied in patients with liver cirrhosis (88). In cirrhotic liver, the expression of both hGHR and hGHRtr was reduced; however, there was a proportionally greater reduction in the expression of hGHRtr. The reduced expression of hGHRtr may be a compensatory mechanism to facilitate GH signaling and may also explain the low serum GHBP found in cirrhosis (44, 45, 46, 88).

Thus, regulation (e.g. ontogenic, nutritional, hormonal) of hGHR mRNA splicing may favor the production of one isoform or the other, leading to modification in the relative proportions of hGHR isoforms that would presumably affect GH signaling and also the proteolytic cleavage of GHR ectodomain. Additional studies are needed to unravel the regulation and physiological role of GHR mRNA splicing.

	GHBP-positive GHIS

Top Abstract Introduction Species divergence Tissue divergence GHR turnover GHBP-generating protease hGHR mRNA splicing GHBP-positive GHIS Summary Clinical implications References

 
Serum GHBP is undetectable or extremely low in most patients with GHIS because of the GHR defect or the failure of ligand binding to the GHR. However, some patients demonstrate normal or high levels of GHBP (17, 18, 89, 90, 91, 92, 93). This situation, which was first considered as exceptional, seems to be more frequent and accounts for about 25% of GHIS patients (90). For example, the mutation D152H caused a failure of receptor dimerization despite normal GH binding and normal GHBP (91, 94). In addition, splice site mutations resulting in complete skipping of exon 8, which codes for the transmembrane domain of the GHR, were reported in patients with GHIS and high serum GHBP levels (89, 93). Recently, Iida et al. (86) and Ayling et al. (87) reported two cases of GHIS caused by heterozygous splice site mutations, resulting in high level of expression of hGHRtr isoform, which showed partial GHI and high serum GHBP. Thus, measurement of serum GHBP in patients with idiopathic short stature may be useful for distinction from classical GHR gene abnormalities and also for preasumption of the mutation site in the GHR.

The implication is that a normal or even elevated serum GHBP level does not exclude patients with GHIS. Subjects with growth failure, low circulating IGF-I, and increased GH secretion should undergo careful analysis, including genetic, hormonal and clinical parameters.

	Summary

Top Abstract Introduction Species divergence Tissue divergence GHR turnover GHBP-generating protease hGHR mRNA splicing GHBP-positive GHIS Summary Clinical implications References

 
Several reservations have been raised concerning the conventional proposition that serum GHBP represents a readily accessible and faithful marker of GHR expression and GH responsiveness, in view of the great difficulty of measuring GHR in humans. Most previous experimental data were collected through comparative analysis of human GHBP against GHR and GHBP determinations in animal models. Yet, GHBP possess species-specific properties, and the mechanism for its generation and regulation display evolutionary divergence. Another important aspect is tissue divergence, in terms of GHR regulation and its cleavage to GHBP. Although GHBP is generated mainly from the liver GHR, many other tissues express GHRs and probably also contribute to the total GHBP level.

Furthermore, human GHBP is generated by proteolytic cleavage of GHR at the cell surface, and, thus, occupancy or modulation of GHR turnover/internalization would impact the level of cell-surface GHRs that are available for proteolysis.

An additional degree of complexity arises from recent reports implicating a metalloprotease activity in GHBP generation. This suggests that the proteolytic system, which controls the specific cleavage mechanism and switch between GHR proteolysis and GHBP shedding, is a regulated process.

Finally, regulation of alternative splicing of GHR primary transcript to the full-length active hGHR and the inactive truncated hGHRtr isoforms might regulate both the production of GHBP and GHR bioactivity, as hGHRtr generates large amounts of GHBP but has a dominant negative effect on GH signaling.

	Clinical implications

Top Abstract Introduction Species divergence Tissue divergence GHR turnover GHBP-generating protease hGHR mRNA splicing GHBP-positive GHIS Summary Clinical implications References

 
Serum GHBP level generally correlates positively with GHR and GH activity. Several clinical GH-resistant conditions, such as liver cirrhosis, renal insufficiency, insulin-dependent diabetes mellitus, hypothyroidism, malnutrition, or critical illness, are accompanied with reduced GHBP levels (7, 8, 9, 10). However, this is not universally true, as in other physiological and pathological conditions GHBP level and GHR function are not tightly interrelated. Decreased GHBP levels are not associated with GHI in early childhood (95, 96, 97) or acromegaly (98, 99).

When accepting IGF-I as an index of GH action, divergence between serum GHBP and IGF-I would also question whether GHBP level reflects GHR function. For example, although IGF-I levels are positively correlated with GHBP levels before puberty, the increase in IGF-I levels during puberty is not accompanied by changes in GHBP levels (100).

Finally, in patients with GHIS, serum GHBP cannot be relied on to detect all GHR mutations and, thus, GHBP does not invariably reflect GHR functionality.

The regulation of human serum GHBP concentration is complex and multifactorial and may involve changes in the expression of GHR, GHR turnover, GHR splicing, and/or modulation of the proteolytic cleavage of GHR. The correct assessment of GHR expression and GH functionality in an individual patient will require in parallel to measurements of serum GHBP, additional detailed diagnostic screening of the entire GH-IGF-I axis.

	Acknowledgments

 
We thank Mrs. I. Fichmann for expert secretarial work.

Received August 10, 1999.

Revised November 10, 1999.

Accepted November 28, 1999.

	References

Top Abstract Introduction Species divergence Tissue divergence GHR turnover GHBP-generating protease hGHR mRNA splicing GHBP-positive GHIS Summary Clinical implications References

 

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