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Center for Endocrinology, Metabolism and Molecular Medicine Department of Medicine Northwestern University Medical School Chicago, Illinois 60611
Address all correspondence and requests for reprint to: G. Baumann, M.D., Northwestern University Medical School, 303 East Chicago Avenue, Chicago, Illinois 60611. E-mail gbaumann{at}nwu.edu
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Introduction |
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Thus, guinea pig pituitary extracts make rats grow (3), but GHs from other species fail to do the same for the guinea pig (1, 3). GH secretion in the guinea pig is pulsatile and under the control of GH releasing hormone, somatostatin, and probably the endogenous ligand for the GH releasing peptide receptor (4). The structure of guinea pig GH is only partially known but seems to exhibit no major deviations from that of other GHs (4). The GHR is expressed in various tissues and able to bind heterologous GH (5). The one biochemical anomaly remaining until recently was the GHBP, which could not be identified in guinea pig plasma using ligand-binding assays (6, 7). In this issue of Endocrinology, Ymer and co-workers demonstrate that this, too, is not a reason for the GH independence of guinea pig growth. Their study shows that GHBP is present in plasma and liver cytosol as determined by both immunochemical and ligand-binding assays, provided the "correct" ligand is employed (8).
The guinea pig GHBP (and GHR) show unusual ligand specificity in that they do not recognize human GH (hGH) (6, 7, 8). In most species, hGH acts as a superagonist for the GHR/GHBP, exhibiting the highest degree of binding (this is probably not just due to the high quality of hGH preparations, but a real phenomenon). The opposite is true in the guinea pig, where ovine and bovine GH, but not hGH, have the expected affinity for the GHBP/GHR (8). The significance, if any, of this anomaly for the guinea pig is not clear because guinea pig GH was not tested, and ovine GH or bovine GH are equally inactive in promoting guinea pig growth as is hGH. However, the report by Ymer et al. reconciles the immunological with the ligand binding data and lays to rest the hypothesis that the guinea pig GHBP is somehow disabled in its binding epitope.
Although not shedding light on the guinea pig paradox, these observations nonetheless highlight a fundamental question, namely what is the biological significance of heterologous ligand binding to a receptor when the activity of the homologous ligand is weaker or unknown. This is a common scenario in the GHR/BP field because of the above mentioned potency of hGH (6, 7, 8, 9, 10, 11). Generally, it is easier to obtain good results with hGH than with the homologous GH, and the data are then extrapolated to the in vivo situation of the animal under study. However, to be physiologically meaningful, only the homologous ligand-receptor pair should be considered. (Studies in humans generally fulfill this criterion.) High quality animal GHs are becoming increasingly available and should be used whenever experiments of a physiological nature are performed. As Ymer et al. mention, this was not possible in their study because guinea pig GH is not readily available. Ironically, in this instance this concern may not be relevant because of the animal’s GH independence.
What then could be the function of the GH/GHR/GHBP system in the guinea pig? Why would such an apparently inert system be evolutionarily retained? One theory is that insufficient time has elapsed for the system to become discarded. There are many examples of such evolutionary remnants. Another, more attractive theory is that the GH/GHR/GHBP system in the guinea pig subserves a function(s) other than growth, such as a metabolic role. This has indeed been suggested (2, 12), and some of the well-known metabolic actions of GH (e.g. insulin antagonism) are demonstrable in the guinea pig (2). More work is required to fully explore the spectrum of metabolic GH actions in this species. A third, highly speculative hypothesis would postulate an as yet unknown, ligand-independent function for the GHR/GHBP. This would explain its evolutionary conservation and its relatively loose link to the affinity of the homologous ligand. In this context, the mysterious presence of the GHR/GHBP in the nucleus comes to mind (13). However, the fact that subjects with GHR deficiency exhibit a phenotype largely limited to the dropout of GH functions (14, 15, 16) does not support this hypothesis.
How does the guinea pig grow in the absence of GH? It’s the somatomedins, of course! IGF-I and IGF-II are present in high concentrations in guinea pig serum, but neither is GH-dependent (17, 18). This is distinctly unusual for IGF-I, which in other species is highly GH dependent. Hypophysectomy in the guinea pig does not decrease and treatment with bovine GH (or hGH) does not increase IGF-I levels. Thus, the real question becomes "What maintains IGF-I expression in the absence of GH?" The answer is presently unknown but may bear on another recent puzzling observation in humans. A significant subset of adult patients with organic hypopituitarism and bona fide GH deficiency, as assessed by provocative tests, have normal IGF-I levels (19). This is not related to obesity and largely unexplained, raising the question regarding the stimulus for IGF-I production. Additional work in the guinea pig should perhaps focus on the regulation of IGF-I expression.
Finally, the report by Ymer et al. illustrates a fact that is not generally appreciated, namely the considerable heterogeneity of GHBP in the circulation. GH-binding components ranging in mol wt from 40 to 350 kDa are shown in a very heterogeneous binding pattern (8), a pattern known to some in the field as rodent-like. This has been previously observed (20, 21) and is very different from what is seen in, e.g. human serum where a single 85 kDa complex predominates. The complexity of the binding pattern in rodent serum, the varying degrees of saturability of the binding components, and the complicated specificities for different (and not always logical) GHs, have dissuaded some early workers in the field from working with rodent serum (among others, Shaw & Baumann, unpublished data). These issues were superseded and subsequently ignored when the cDNAs for rodent GHBPs became known (22, 23), and when charcoal adsorption and immunoassays blind to these complexities were introduced. The paper by Ymer et al. revisits this issue and dramatically illustrates the complex binding pattern not only in guinea pig but also rat serum (see Fig. 2 in the Ymer paper). The authors also offer some explanations for these intricacies, though it will likely be a daunting task to fully unravel the protein interactions taking place when GH enters the rodent circulation.
Thus, the paper by Ymer et al. in this issue raises many provocative questions in the GH field, some of them very old but still unresolved. The guinea pig may not be the only animal displaying such aberrant endocrine growth behavior. Classification of the guinea pig has been a challenge for taxonomists (12), but there must be related species that can help shed light on how growth and development is accomplished without a pituitary gland.
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This article has been cited by other articles:
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  L. L. Anderson, D. L. Hard, A. H. Trenkle, and S.-J. Cho Long-Term Growth after Hypophyseal Stalk Transection and Hypophysectomy of Beef Calves Endocrinology, May 1, 1999; 140(5): 2405 - 2414. [Abstract] [Full Text]
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