Journal of Clinical Endocrinology & Metabolism
, doi:10.1210/jc.2007-0526
The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 12 4529-4535
Copyright © 2007 by The Endocrine Society
REVIEW: The Somatomedin Hypothesis 2007: 50 Years Later
Solomon A. Kaplan and
Pinchas Cohen
David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California 90095
Address all correspondence and requests for reprints to: Solomon A. Kaplan, M.D., Professor Emeritus, Department of Pediatrics, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, Los Angeles, California 90095-1752. E-mail: skaplan{at}mednet.ucla.edu.
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Abstract
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Context: The somatomedin/IGF hypothesis was based on the observation that GH was inactive when added to an in vitro incubation system but required a GH-dependent substance in the circulation to mediate its activity. Newer experimental evidence has led to several modifications of the hypothesis, but none of the proposed modifications accounts for all of the integrated actions of GH and IGF-I. In this paper, we propose an augmentative/counteractive modification of the existing hypothesis that takes into account all the actions of the GH-IGF system.
Evidence Acquisition: The modification is based on experimental evidence published since the hypothesis was originally developed.
Evidence Synthesis: The modification is based on an integration of the results of published experimental evidence regarding the actions of GH and the IGF complex.
Conclusion: We propose a new augmentative/counteractive modification of the hypothesis that the actions of the GH-IGF system provide a distinct evolutionary advantage to the organism by augmenting the anabolic actions of GH while countering its potentially deleterious effects of hyperglycemia and depletion of lipid stores.
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Introduction
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THE TERM SOMATOMEDIN was coined by investigators in 1972 to designate a substance in the serum considered to be the intermediary of somatotropin action on its target tissues (1). They formulated the hypothesis that GH did not exert its effects directly on tissues but did so through an intermediary, first named sulfation factor and later, somatomedin. This substance was produced in the liver and secreted into the circulation.
The hypothesis was based primarily on a series of elegant experiments conducted half a century ago. In 1957, Salmon and Daughaday (2) showed that incorporation of radioactive inorganic sulfate into acid mucopolysaccharides of rat cartilages could be stimulated by addition of serum from hypophysectomized rats that had been injected with GH in vivo. Addition of GH to the medium in which the cartilages were being incubated, however, did not result in enhanced incorporation of the radioactive precursor. The magnitude of the increased incorporation was found to be proportional to the amount of added serum, and before the advent of immunoassays for GH, the degree of enhanced incorporation was used as a bioassay of GH in the serum (3, 4). This assay was supplanted by RIAs when they became available (5). The putative factor responsible for the stimulating activity was named the sulfation factor because radioactive inorganic sulfate was used as the precursor in the incorporation studies. Similar results were found when incorporation of other precursors was tested, such as leucine into protein-polysaccharide complexes, uridine into RNA, and thymidine into DNA (6, 7). Subsequently, multiple factors were isolated with similar activities and were labeled somatomedins A and C (8).
As was the case with GH, before development of the immunoassay for insulin (9), attempts to measure its activity in serum were made by bioassay of its effects in vitro, such as the uptake of glucose in isolated tissues (10). When more precise RIA measurements of insulin were developed, it was found that only a small fraction of this in vitro activity of serum was ascribable to insulin itself (11). Addition of specific neutralizing insulin antibodies to the in vitro system resulted in only minimal suppression of the bioactivity that had been previously ascribed to insulin (12). These activities were attributed to the presence in the serum of nonsuppressible insulin-like activities (NSILAs). Subsequently, because these factors were found to have growth and mitogenic effects, they were designated as IGFs (13).
Two NSILAs designated as IGF-I and IGF-II were shown to have structural similarities to the insulin molecule (14, 15). They consist of A-domains homologous to the A-chain of insulin, B-domains homologous to the B-chain, C-domains homologous to the C-chain of proinsulin, and D-domains extending from the C terminals of the A-chains. Other investigators later showed that somatomedin C had the same amino acid sequence as IGF-I (16). The largest fraction of IGF-I in the serum was found to be derived from the liver where the expression of IGF-I was found to be regulated by GH (17). Based on the evidence available at the time, the somatomedin hypothesis was formulated that the actions of GH on cartilage and other tissues were mediated through IGF-I synthesized in the liver and not by direct action of GH on tissues (1).
In the following, we present evidence to support the modification of the classic somatomedin hypothesis to account for the augmentative-counteractive actions of GH and IGF-I.
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Evidence Based on in Vitro Precursor Incorporation into Cartilage
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Choice of the components of the media of in vitro incubation systems as well as the duration of incubation may be arbitrary, as was demonstrated by Salmon and Burkhalter (18), who revisited the experiments originally done in 1957. They found that purified bovine GH, recombinant bovine GH, and recombinant human GH all stimulated precursor incorporation into cartilage of hypophysectomized rats. These results were different from those obtained in the original experiments, presumably because of the use of different incubation media. In the newer experiments, they used HEPES instead of phophosaline buffers, defined concentration of amino acids instead of serum, and 0.2 mg/ml crystalline BSA. In the first 24 h of incubation, although GH in concentrations of 10, 100, and 1000 ng/ml did, indeed, stimulate incorporation of radioactive inorganic sulfate into cartilage, the degree of stimulation by IGF-I in concentrations of 1, 10, and 100 ng/ml was considerably greater than that by GH. After 48 h of incubation, however, the differences between stimulation by GH and IGF-I were virtually abolished. Incorporation of thymidine into cartilage was also stimulated to a much greater degree by IGF-I than by GH. After 48 h of incubation, however, the degree of stimulation by IGF-I had fallen precipitously, whereas that by GH was continuing to increase. To determine the relative contributions of GH and IGF-I to precursor incorporation into cartilage they added an antibody to IGF-I to the incubation medium. Their overall conclusion from the results of their experiments was that "the effects of GH on skeletal growth represent a combination of direct and indirect actions, with an intermediary role of IGF-I in either case."
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Evidence Based on Studies of the Epiphyseal Plate in Vivo
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In vivo studies of rat tibial growth plate were carried out by Isaksson et al. (19). Local injection hGH directly into the cartilage growth plates of the hind limbs of hypophysectomized rats produced significant increases in lengths of the injected limbs compared with the control, contralateral limbs. Similar results were obtained by other investigators (20, 21). In more recent experiments by the same group of investigators, GH was administered with labeled thymidine in vivo into the rat tibial growth plate through cannulas and injection needles with an outer diameter of 1.2 mm. GH significantly increased the number of labeled cells in the germinal cell layer. Cells of this population cycle slowly and were considered by the investigators to be progenitors of the cells of the growth plate as well as other components of growing bone. Administration of IGF-I did not stimulate multiplication of the cells in the germinal layer of the epiphyseal plate, and the authors concluded that GH has a direct action on these cells, whereas IGF acts only on the proliferation of chondrocytes (22).
More recently, the proliferation of epiphyseal growth plate chondrocytes has been studied in animals in which the IGF-I gene (IGF-I null) and GH receptor gene (ghr null) were deleted. Wang et al. (23) observed that chondrocyte numbers and proliferation were normal in IGF-I-null mice and concluded that IGF-I promotes growth by augmenting chondrocyte hypertrophy. On the other hand, Lupu et al. (24) showed that both IGF-I and GH receptor genes are expressed in the same zone of proliferating chondrocytes. These investigators found that the increase in body weight of mice in which the IGF-I gene had been mutated was considerably less than in mice in which the GH receptor gene had been mutated, whereas the growth of mice that were double homozygous for the knockout of both genes was further reduced (Fig. 1
). Differences in body length, although present, were less marked. They concluded that the IGF system is the major determinant of growth and that GH and IGF effectors, acting in concert, are responsible for the convergence of most growth signaling pathways and provided the first convincing evidence suggestive of IGF-independent actions of GH on auxological growth.
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FIG. 1. Relative contributions of GH and IGF to postnatal growth as assessed by the postnatal size of knockout mouse models, based on data from Lupu et al. (24 ).
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In a later study, Wang et al. (25) obtained results leading to conclusions different from those of Lupu et al. (24). They found that longitudinal tibial growth rate was reduced by about 35% in IGF-I-null mice and about 63% in ghr-null mice. Reductions in growth rate of ghr-null mice (approximately 60%) were reported by Sims et al. (26). Mohan et al. (27) also found a greater reduction in growth rate in GH-deficient mice compared with igf-null mice. On the other hand, Hutchison et al. (28) found that systemic IGF-I was a major regulator of bovine epiphyseal chondrocyte proliferation and that fibroblast growth factor enhanced the actions of IGF-I by increasing its binding to these cells. Interestingly, they found no specific binding of GH to these cells. In another recent study, Wang et al. (29) found that IGF-I exerts a profound stimulating effect on embryonic bone by promoting chondrocyte proliferation and maturation.
Interpretation of these results is complicated by the assertion that no hard evidence exists to support the postulate that cells in the resting zone are the immediate precursors of proliferative chondrocytes (24). Lupu et al. (24) have suggested that the apparent expansion of the resting zone in IGF-I-null animals is an artifact because as the secondary ossification center expands, the resting zone is continually shrinking. Until discrepancies between the results of these different groups of investigators can be resolved, questions about the precise mechanisms of action of GH and IGF-I on differentiation and proliferation of the epiphyseal plate will remain undecided.
Despite this ongoing controversy regarding the precise mechanism of action of GH and the IGFs, there is substantial evidence that GH acts directly on the epiphyseal cartilage. Some of the evidence has already been discussed in some detail above (19, 20, 21, 22, 23). In addition, in vivo experiments in which GH was administered to epiphyseal growth zones through microcannulas have shown that GH stimulates bone growth directly (30, 31).
Controversy also exists regarding the contribution of hepatic-generated IGF-I to epiphyseal bone growth. Yakar et al. (32) generated transgenic mice expressing cre recombinase in the liver under the control of the albumin promoter. In the liver IGF-I-deficient (LID) mice, deletion of the liver gene of IGF-I reduced the circulating level of IGF-I to about 25% of that found in littermate wild-type animals. When the LID mice were killed at the age of 6 wk, their body and femoral lengths were not significantly diminished compared with that of wild-type littermates. Their body weights also did not differ significantly from those of the controls, and the same applied to the weights of their viscera.
Sjogren et al. (33) used a second system in which an inducible interferon promoter was used instead of albumin to drive the expression of cre. The effects of this deletion were essentially the same as those in the original experiments. These investigators proposed a modification of the GH/somatomedin hypothesis that largely discounted the contribution of hepatic-derived IGF-I to the action of GH on its target tissues. They proposed a direct action of GH on bone with the additional involvement of autocrine/paracrine systems. In a subsequent review, LeRoith et al. (34) also proposed a second arm of action by GH in nonosseous systems such as muscle, in which IGF retained its role as the mediator of its effects.
To deal with the possibility that the 4-fold increase in circulating GH levels in the knockout mice might result in compensation from nonhepatic tissues, the investigators measured the levels of IGF-I mRNA in a variety of tissues including heart, muscle, fat, spleen, and kidney in their original experiments (32). The levels of IGF-I mRNA in these tissues were not different from those of the wild-type littermates.
Unlike insulin, which circulates in an unbound form in the circulation, the IGFs circulate in the plasma bound to a complex group of IGF-binding proteins (IGFBPs) (35). At least six different binding proteins have been isolated and their amino acid sequences determined (36). This association with their IGFBPs inhibits the actions of IGFs under most circumstances, presumably by competing with IGF receptors for IGF peptides (37). However, it is evident that IGFBPs, in addition to acting as IGF-binding proteins, also associate with cell membranes (37). IGFBP-3 and IGFBP-5 have been shown to be localized to nuclei in a number of cell lines (38, 39). IGFBP-3 has also extensively been shown to act independently of IGF to inhibit cell growth and induce apoptosis by internalizing into cells and interacting with the nuclear receptors retinoid X receptor and Nur77 (40). Other investigators have also shown direct effects of IGFBP-3 on growth and metabolism of target cells (41, 42).
The great majority of IGF-I circulates in the serum in a complex with IGFBP-3 and the acid-labile subunit (ALS) (43). ALS prolongs the half-life of IGF-I in the serum and regulates its delivery to tissues by confining it to the circulatory system. Experiments supporting the lack of a significant role of hepatic-generated mRNA by deletion of the ALS gene with consequent approximately 60% reduction in circulating IGF-I levels were reported by Ueki et al. (44). In later studies, however, in which the genes for IGF-I and ALS were both disrupted, the linear growth of LID plus ALS knockout mice was reported to be significantly reduced (34). The authors attributed these newer results to the fact that in these animals, the IGF-I levels were reduced to 10–15% of normal, to a greater degree than in their original experiments. There was a marked reduction in the IGFBPs, and as expected, the levels of GH were markedly increased.
The suggestion that GH exerts its effects on nonosseous tissues through a mediator such as IGF (34, 45) is debatable because the effects of the putative mediator on muscle and other tissues are the opposite of those of GH itself. The effects of circulating IGF-I on lipolysis and gluconeogenesis are the opposite of those of circulating GH. This issue is discussed in detail below under Evidence That a Significant Number of the Effects of GH and IGF-I on Body Tissues Are Antagonistic. In addition, GH has been shown to have direct effects in vitro on nonosseous tissues such as erythroid colonies (46) and normal and leukemic human lymphocyte T cells (47) as well as arterial medial cells (48). In a recently published study, Klover and Hennighausen (49) reported evidence that GH has a direct effect on skeletal muscle. They based their conclusions on the known observation that the transcription factors signal transducers and activators of transcription (STAT)5a and STAT5b are essential mediators of the actions of GH, including the transcription of the IGF-I gene. When the genes for these transcription factors were deleted in mice, they found that STAT5 protein expression was lost selectively in skeletal muscle, whereas expression in the liver was not affected. The growth impairment of the animals was not confined to the skeleton but involved skeletal muscle to a considerable degree. Their data suggest that skeletal muscle is a major site of direct GH action. In a recent report, Kim et al. (50) have shown that GH treatment did not increase muscle mass in mice that lacked IGF-I receptor function. Their studies showed that GH exerts its effects on muscle function and mass by activation of the IGF-I receptor.
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Evidence That IGF-I Is Produced in Virtually All Tissues of the Body
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In 1984, D’Ercole et al. (51) reported that levels of somatomedin C in kidney, liver, heart, and testes of hypophysectomized rats increased to a maximum 12 h after ip injection of ovine GH. The tissue maximum was reached some 6 h before the maximal increment in the serum. The investigators suggested that the somatomedins acted at the sites of tissue production through local autocrine or paracrine, rather than by endocrine, mechanisms. The issue of whether these peptides are produced locally rather than transported from other sites such as the liver was addressed by Murphy et al. (52). They measured IGF-I and IGF-II mRNA expression in forebrain, lung, ovary, testis, uterus, kidney, heart, mammary gland, and skeletal muscle. Measurable activities of IGF-I mRNA were found in each of these organs, the highest levels being found in liver. IGF-II mRNA activity was detected in forebrain, uterus, kidney, heart, and skeletal muscle. Minimal activity was present in the liver, and by far, the highest levels were found in the forebrain. These studies support the hypothesis that the IGFs act on target tissues, at least in part, by autocrine or paracrine mechanisms. Other investigators have confirmed the presence of IGF-I mRNA activity in adult rat tissues such as heart, muscle, fat, spleen, and kidney (34) and have shown that these activities were not reduced in animals in which the IGF-I gene had been deleted from the liver.
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Evidence That GH Receptors Are Present in Virtually All Body Tissues
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As is the case with IGF-I, there is evidence that virtually all body tissues are responsive to GH. A review of all the publications on this subject is beyond the scope of this review, and only one will be cited here. Ballesteros et al. (53) studied the distribution of m RNA for GH receptor in a variety of human liver, fat, muscle, kidney, heart, prostate, fetal liver, lymphocytes, and skin fibroblasts. GHR mRNA was readily detectable in all tissues, with liver, fat, muscle, and kidney showing the highest levels of expression. Other studies have shown the presence of GHR mRNA in a variety of human normal and malignant tissues (54, 55, 56).
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Evidence That a Significant Number of the Effects of GH and IGF-I on Body Tissues Are Antagonistic
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The metabolic effects of GH may be classified as insulin-like and insulin-antagonistic (19). IGFs were originally identified by their insulin-like effects and were referred to as NSILAs (11, 12, 13, 14, 15). Among the established effects of GH are gluconeogenesis and lipolysis (34). On the other hand IGF-I exerts the opposite, insulin-like effects of increased tissue glucose uptake, inhibition of gluconeogenesis, and enhanced adipogenesis (34, 57, 58, 59).
To account for the paradox that GH exerts its effects through IGFs, some of which are opposite to the known actions of GH, the possibility was originally entertained that different hormone subfractions might be responsible for these opposite effects (60). Experiments to verify this hypothesis have not been confirmed, and it is evident that the insulin-antagonist effects of GH are an intrinsic property of the molecule (61). Evidence supporting the hypothesis that different effects of GH might be due to activation of different GH receptors has also failed to materialize.
In addition to the in vitro experiments referred to above (11, 12, 13) the hypoglycemic effects of IGF-I administration to human subjects have been reported in a large number of publications. An extensive review of all the evidence is beyond the scope of this paper, and we shall confine this report to studies in humans, including normal subjects and those with various syndromes of diabetes. An early report by the team of Swiss investigators responsible for the discovery and characterization of the IGFs showed that IGF-I administration to healthy adults resulted in hypoglycemia (62). In a study of healthy young and middle-aged adults, Boulware et al. (63) showed that the metabolic responses to recombinant human IGF-I and insulin were remarkably similar. In paired euglycemic clamp studies, they found that both hormones had nearly identical effects on glucose uptake, glucose production, plasma free fatty acid concentrations, and fat oxidation rates. These effects, however, may represent central hypothalamic actions of IGFs and insulin (64). Simpson et al. (65) investigated the effects of GH, IGF-I, and a placebo on subjects with type 1 diabetes, using stable isotopes and euglycemic clamp procedures. They found that IGF-I reduced hepatic glucose production and increased peripheral glucose uptake. Moses et al. (66) showed that sc administration of IGF-I significantly lowered plasma glucose concentrations in 12 subjects with type II diabetes. Mean glucose during a modal day was decreased from 14.71 ± 4.5 to 9.1 ± 3.21 mmol/liter. After 6 wk, glycosylated hemoglobin concentrations were reduced from 10.4 to 8.1%. Zenobi et al. (67) showed that administration of recombinant human IGF-I to two subjects with insulin-resistant diabetes type A resulted in a reduction of fasting glucose concentrations by nearly 50%.
In regard to the lipogenic properties of IGF-I, long-term treatment by IGF-I of subjects with the GH insensitivity syndrome led to the expected acceleration of growth that was associated with a substantial gain in fat mass (58). In another study in which GH-insensitive subjects were treated with IGF-I, there was a relative increase in mean body weight for height (59). Treatment of the only known human subject with homozygous partial deletion of the IGF-I gene resulted in an initial decrease in total body fat, but this trend was reversed after 12 months of therapy (68). In a recent report of the longest treatment of patients with the GH insensitivity syndrome, Laron et al. (69) have shown that IGF-I therapy increased body adipose tissue to double or triple the normal values. They concluded that IGF-I, similar to insulin, exerts an adipogenic effect. The effects of IGF and GH on metabolism are further complicated by the fact that GH-induced IGFBP-3 has its own direct and independent effects on adipocyte function and insulin sensitivity (64, 65, 70).
Figure 2 summarizes the overall actions and interactions of GH and IGFs on somatic growth and metabolism. The effects of GH and IGF-I on target tissues other than bone and cartilage are based largely on conclusions derived from in vivo studies in which genes for GH receptors and IGF-I have been disrupted.
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FIG. 2. A new somatomedin hypothesis: effects of GH and IGF-I on growth and metabolism. See details in text. (+), Stimulatory effect; (–), inhibitory effect; AN, anabolic effect; GLU, glucose utilization; LIP, lipogenesis.
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The Augmentative/Counteractive Hypothesis
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Evidence has been presented that the IGFs are counteractive for some of the effects of GH, their insulin-like actions acting to negate the GH stimulation of gluconeogenesis and lipolysis. The augmentative/counteractive system of GH-IGF augments the anabolic action of GH while attenuating the potentially undesirable GH effects of gluconeogenesis and lipolysis. Because IGFs have insulin-like effects that stimulate protein synthesis and inhibit proteolysis (71, 72) while countering the hyperglycemic and lipolytic effects of GH, this augmentative/counteractive mechanism serves to enhance the anabolic effects of GH. This concept supports the one-two punch anabolic effect of GH postulated by Daughaday (73). Other examples of augmentative actions of one hormone on another have been described such as the cooperative actions of TSH with insulin or IGF-I on the progression and proliferation of thyrocyte culture systems such as the FTRL-5 line (74).
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Conclusions
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It is evident that IGF-I cannot be the sole mediator of GH action because IGF-I repletion does not restore the deficits found in GH insensitivity. It is also evident that GH has direct effects in vivo that are independent of IGF-I, many of which are exerted through local production of IGFs rather than under the influence of a factor in the circulation. We have also cited evidence that the anabolic actions of IGF-I are augmentative to those of GH, whereas the effects on lipid and carbohydrate metabolism run counter to the established actions of GH. Therefore, an alternative hypothesis is that stimulation of IGF-I production leads to augmentative as well as counteractive actions to those of GH.
The original somatomedin/IGF hypothesis was based on the observation made some 50 yr ago that GH was inactive when added to an in vitro system and that its effects were mediated by a GH-dependent factor in the circulation. The originators of the hypothesis were concerned largely with growth-promoting effects of somatomedin on skeletal tissues, although they included a consideration of the effects of somatomedin on the anabolic responses of nonskeletal tissues.
The hypothesis requires modification because of the following experimental observations. 1) Investigators have shown that, under the proper conditions, GH does indeed exert a direct action on precursor incorporation in the in vitro cartilage system. 2) There is a substantial body of evidence that GH acts directly (and independently of IGF-I) on the growth of bone. 3) Although the liver is the main source of IGF-I in the circulation, IGFs are produced in virtually every tissue of the organism. 4) GH receptors have been shown to be present in virtually every tissue. Thus, mechanisms exist for direct action of GH on organs and tissues without the need for the presence of a GH-dependent factor generated by the liver and secreted into the bloodstream (5). The IGFs have insulin-like and IGF-enhancing activities in vivo and in vitro, such as increased glucose consumption, diminished gluconeogenesis, and lipogenesis, as opposed to the biological effects of GH that include increased gluconeogenesis, enhanced lipolysis, and inhibition of insulin action.
Attempts to devise a hypothesis to account for some or all of these observations have led to proposed modifications of the somatomedin/IGF hypothesis. Because none of these modifications presents an explanation to account for all of the actions of GH, we propose a new unifying hypothesis to explain the interactions of GH and the IGFs. We propose that the IGFs, rather than effectors of GH action, are augmentative hormones that amplify the anabolic actions of GH while countering its potentially deleterious effects. Because the IGFs are counteractive for some but not all the effects of GH, their insulin-like effects may act to negate GH-stimulated gluconeogenesis and enhanced lipolysis. On the other hand, their anabolic actions are generally augmentative, enhancing those of GH through the GH-independent stimulation of protein synthesis and inhibition of proteolysis.
The augmentative/counteractive mechanism may well be considered an adaptation to enhance the effects of GH by secretion of IGFs that enhance its positive anabolic effects while opposing its potentially negative diabetogenic and lipolytic effects. In the scheme of evolutionary survival, it would serve to benefit the organism by enhancing the positive effects of protein anabolism and growth while negating the potentially deleterious consequences of hyperglycemia and loss of lipid stores.
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Footnotes
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Disclosure Statement: The authors have nothing to declare.
First Published Online November 6, 2007
Abbreviations: ALS, Acid-labile subunit; IGFBP, IGF-binding protein; LID, liver IGF-I-deficient; NSILA, nonsuppressible insulin-like activity; STAT, signal transducers and activators of transcription.
Received March 8, 2007.
Accepted October 29, 2007.
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Abstract
Introduction
