Insulin-Like Growth Factors and Skeletal Growth: Possibilities for Therapeutic Interventions

Judson J. Van Wyk and Eric P. Smith

Division of Endocrinology, Department of Pediatrics, University of North Carolina School of Medicine (J.J.V.W.), Chapel Hill, North Carolina 27599; and the Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Cincinnati School of Medicine (E.P.S.), Cincinnati, Ohio 45229

Address all correspondence and requests for reprints to: Dr. Judson J. Van Wyk, Department of Pediatrics, University of North Carolina School of Medicine, C.B.# 7220, Chapel Hill, North Carolina 27599.


    Introduction
 Top
 Introduction
 Overview of IGF ligands,...
 IGF-binding proteins (IGFBPs)
 Role of IGFs in...
 Evidence from gene deletion...
 Synthesis and biological actions...
 Interactions among IGFs, GH,...
 Potential therapeutic usages and...
 References
 
In this, her last issue as editor-in-chief of JCEM, Dr. Maria New has invited some of her colleagues in pediatric endocrinology to contribute short commentaries on issues of current interest. It is a pleasure to honor Dr. New on this occasion, both for her leadership in taking our journal to a new level of excellence and for her many scientific contributions that have enhanced our understanding and treatment of adrenal disorders.

The central focus of pediatric endocrinology has been the hormonal control of growth and development, and in recent decades it has been possible to correlate the serum concentrations of nearly every known hormone with each phase of normal growth and with most types of aberrant growth. The insulin-like growth factors (IGFs) or somatomedins, as they are frequently called, have been an important focus of pediatric endocrinologists because of their pivotal role in skeletal growth. The present essay addresses the roles of these peptides in the growth of the skeleton and considers how we might take advantage of their many actions for therapeutic purposes.


    Overview of IGF ligands, receptors, and biological actions
 Top
 Introduction
 Overview of IGF ligands,...
 IGF-binding proteins (IGFBPs)
 Role of IGFs in...
 Evidence from gene deletion...
 Synthesis and biological actions...
 Interactions among IGFs, GH,...
 Potential therapeutic usages and...
 References
 
The two known somatomedins, IGF-I and IGF-II, are structurally homologous to proinsulin. They were initially identified on the basis of three unique properties: their mediation of the skeletal growth-promoting actions of GH, their mitogenic properties, and their mimicry of the actions of insulin. These peptides were isolated in Zurich by Rinderknecht and Humbel on the basis of their insulin-like activity, but were renamed IGF-I and IGF-II when it became apparent that their growth-promoting properties were more important than their insulin-like activities (1). Somatomedin C was isolated in Chapel Hill from human blood fractions by Van Wyk et al. guided by assays based on the stimulation of proteoglycan and DNA synthesis in cartilage as suggested by William Daughaday. Somatomedin C was found on sequence analysis to be identical to IGF-I as reported by the Zurich group (2). As no peptide comparable to IGF-II was isolated under the somatomedin rubric, it is now conventional to use IGF-I and IGF-II when referring to the specific peptides and the term somatomedins or IGFs when referring to these peptides generically (3).

The IGFs are more primitive hormones than insulin and have a much broader spectrum of action. Insulin presumably evolved from the IGFs to fulfill a more specialized function when the need arose to store energy during periods of fasting. The ancestral relationship of insulin to IGFs to insulin is similar to that of PTH to PTH-related protein (PTHrP), with PTHrP having a more ubiquitous spectrum of activities than PTH.

Both of the somatomedins are developmentally regulated and subject to precise tissue-specific expression. Methods for the quantitation of IGF-I were developed before comparable methods became available for IGF-II (4, 5), and to this day much less is known about the physiological roles of IGF-II than those of IGF-I. Blood levels of IGF-II are considerably higher than those of IGF-I, and the concentrations of IGF-II in extracts of skeletal tissue are higher than those of IGF-I. Blood levels of IGF-I are more stringently regulated by GH and nutritional factors than are those of IGF-II, but IGF-II is more insulin like than IGF-I. The idea has been perpetuated that IGF-II is the fetal hormone and IGF-I is the somatomedin of postnatal life. It is now clear, however, that both IGF-I and IGF-II are important for normal fetal growth and that both have distinctive functions postnatally.

Most of the IGF-I circulating in blood comes from the liver, where the expression of the IGF-I gene is regulated by GH (6). The IGFs are also produced in peripheral tissues, where the expression of their genes is regulated by many hormones. IGFs are required for the proliferation of most cell types, and they promote cell survival by inhibiting programmed cell death (7). They also regulate a vast number of highly differentiated cell functions.

The nature of the responses to IGFs is dependent on physiological circumstance. It is pertinent to the role of IGFs in skeletal growth that sparsely plated chondrocytes respond to IGF-I with increased DNA synthesis, but not with increased sulfate incorporation into proteoglycans. On the other hand, when the same cells reach confluence, IGF-I stimulates matrix synthesis but has no effect on DNA synthesis. Such observations imply that IGFs may act as both a mitogen in the proliferative zone and a stimulant of proteoglycan synthesis in the hypertropic zones of the growth plate, with the specific effect being dependant on the cellular and hormonal environments.

The biological importance of the somatomedins is often underestimated because their effects, compared with those of other growth factors, are often weak or difficult to demonstrate. This is because the IGFs characteristically exercise a permissive or modulating role on biological processes rather than serving as the primary agonist. This was illustrated in the interactions of IGF-I with pituitary hormones in the gonads and thyroid. Adashi et al. showed in rat granulosa cells that the effect of FSH plus IGF-I was nearly 10-fold greater than the effect of FSH by itself, even though IGF-I by itself was seemingly inactive (8). Similarly, whereas IGF-I is a relatively weak mitogen in rat thyroid cells, its mitogenicity is potentiated more than 30-fold after these cells are exposed to TSH (9).

Both IGF-I and IGF-II produce their biological effects through type I receptors that are homologous with the insulin receptor (10). Insulin and the IGFs all cross-react with the type I and insulin receptors and with hybrid receptors containing subunits of each receptor. Type I receptors are present in most, if not all, tissues. The cytoplasmic domain of the type I receptors contains a tyrosine kinase that initiates a phosphorylation cascade through the Ras-Raf-mitogen-activated protein kinase and phosphoinositol 3'-kinase pathways (7). A variety of docking proteins, including insulin receptor substrate-1 and -2 and Shc, act as immediate substrates for the receptor tyrosine kinase. Type I receptors have been observed in proliferating chondrocytes from several species, with predominant expression in developing chondrocytes (11, 12). The IGF-II/mannose-6-PO4 receptor protects against toxic levels of IGF-II, but is not believed to mediate the actions of IGF.


    IGF-binding proteins (IGFBPs)
 Top
 Introduction
 Overview of IGF ligands,...
 IGF-binding proteins (IGFBPs)
 Role of IGFs in...
 Evidence from gene deletion...
 Synthesis and biological actions...
 Interactions among IGFs, GH,...
 Potential therapeutic usages and...
 References
 
Secretion of IGFBPs accompanies the secretion of IGFs in most, if not all, tissues in which IGFs are made. The patterns of IGFBP secretion vary considerably between different tissues and in response to differing physiological circumstances, thus imparting a high degree of specificity to the actions of the IGFs. The specific endoproteases that degrade the several IGFBPs are likewise hormonally regulated and provide additional mechanisms for regulating IGF actions.

Each of the six major IGFBPs has been identified in skeletal tissues. In osteoblast-like cells, IGFBP-3, -4, and -5 are probably the most important based on their relative abundance and biological potencies (13). The addition of exogenous IGFBPs to bone cells has produced both stimulatory and inhibitory effects on IGF actions (14). IGFBP-4 does not bind to cells, and it inhibits bone cell proliferation by competing with the IGF receptor for binding the IGFs (15). By contrast, IGFBP-3 and -5 enhance receptor binding and the anabolic effect of the IGFs on bone (16).

IGFBPs may be responsible for the high levels of IGF-I and IGF-II in bone matrix. IGFBP-3 binds to proteoglycans prepared from a variety of cartilage tissues, and the bound IGFBP-3 sequesters IGF-I in extracellular matrix (17). Matrix proteoglycans do not bind IGFs in the absence of IGFBP-3. IGFBP-5 has strong affinity for hydroxyapatite, and in the absence of IGFBP-5, the IGFs do not bind to hydroxyapatite (18).

The importance of binding proteins as modulators of IGF action suggests that the most promising possibilities for exploiting IGFs as therapeutic agents in skeletal disease may depend on finding ways to selectively manipulate IGFBPs. This might be accomplished by altering their expression or proteolytic degradation or by discovering substances that compete with IGFs for binding to the binding proteins. Another approach has been to modify IGF-I by truncating the amino-terminus. Such peptides [e.g. des(1, 2, 3)-IGF-I] have markedly reduced affinity for binding proteins and in many systems are far more active than native IGFs (19).


    Role of IGFs in skeletal growth
 Top
 Introduction
 Overview of IGF ligands,...
 IGF-binding proteins (IGFBPs)
 Role of IGFs in...
 Evidence from gene deletion...
 Synthesis and biological actions...
 Interactions among IGFs, GH,...
 Potential therapeutic usages and...
 References
 
An early issue was whether GH acts directly on skeletal tissues to stimulate growth, or whether its growth-promoting actions require the mediation of IGF-I as stipulated in the somatomedin hypothesis of GH action. Although it is now well established that IGFs are essential for normal skeletal growth, arguments have persisted concerning whether the IGF-I that mediates skeletal growth is derived from the peripheral circulation or is synthesized in the growth plate in response to GH and other hormones that stimulate its synthesis locally (20). In our opinion this is not a substantive issue, because both endocrine and paracrine modalities have been well documented in vivo. Targeted knockout of the IGF-I gene in the liver (but not in other tissues) by the Cre/loxP system does not impair the growth-promoting actions of GH, even though blood levels of IGF-I are substantially decreased (21).

Controversies also remain, however, over whether IGF-I by itself can stimulate the proliferation of chondrocytes or can do so only after GH has first stimulated the differentiation of prechondrocytes into more mature cartilage cells, as postulated by Green’s dual effector theory of GH action (22). The ability of IGF-I to restore growth in dwarfed children who lack functional GH receptors suggests that IGF-I delivered from the circulation is sufficient to produce growth without the need for GH (23). Such responses, however, attenuate over time and are less than those observed with GH treatment of GH deficiency states. Ohlsson has postulated that GH is required for providing an adequate stem cell population of prechondrocytes (24).


    Evidence from gene deletion studies on the role of IGFs in skeletal growth
 Top
 Introduction
 Overview of IGF ligands,...
 IGF-binding proteins (IGFBPs)
 Role of IGFs in...
 Evidence from gene deletion...
 Synthesis and biological actions...
 Interactions among IGFs, GH,...
 Potential therapeutic usages and...
 References
 
Definition of the roles of the somatomedins in skeletal growth has been obtained from gene knockout models in mice lacking the genes encoding IGF-I, IGF-II, or their respective receptors. Knockout studies confirmed that both IGF-I and IGF-II are essential for normal prenatal growth, as mice deficient in either IGF-I or IGF-II were only 60% of normal size at birth (25). Knockout of IGF-II did not alter postnatal growth, as the size ratio between normal and mutant littermates was maintained into adulthood. Unlike the IGF-II-deficient mice, most of the IGF-I mutant mice died at birth, and those that survived showed severe postnatal growth retardation.

Mice with gene knockout of the type I IGF receptor had even greater fetal growth deficits (45% of normal birth weight) than knockouts of either IGF-I or IGF-II alone (26, 27). Mice lacking the type I IGF receptor exhibited delayed appearance of their ossification centers and delay in epiphyseal maturation, and they usually died at birth due to generalized hypoplasia of all muscles, including those responsible for respiration. Experiments with combined deletions made clear that the type I receptor mediates the essential functions for IGF-I and most of those for IGF-II, at least during fetal development.

Gene knockout studies revealed that a primary function of the IGF-II receptor (IGF-II/M6Pr) is to regulate IGF-II levels, which can be lethal if too high (28). A null mutation in the IGF-II/M6Pr gene resulted in large birth weights and lethality of nearly all mutant embryos. Simultaneous deletion of the IGF-II gene completely rescued the phenotype associated with the IGF-II/M6Pr gene knockout, because high levels of IGF-II were avoided (29).

Genetic models of selective GH or IGF-I deficiency in humans confirm the rodent knockouts. A child reported by Woods et al., who had an inactivating mutation of the IGF-I gene, suffered severe intrauterine and postnatal growth retardation (30). In contrast, children who lack the GH gene or who are unresponsive to GH are essentially normal at birth, and their growth retardation is limited to postnatal life. From this we can conclude that IGF-I and IGF-II, but not GH, are essential for normal intrauterine skeletal growth.

Immortalized T lymphocytes from a tribe of African Pygmies have a decreased number of type I IGF receptors, and those present are not phosphorylated and do not transmit a signal in response to IGF-I (31). Baserga and colleagues have shown that the proliferation of transgenic cells lacking the IGF type I receptor is markedly impaired, and that they do not respond to epidermal growth factor and other mitogens (32).


    Synthesis and biological actions of IGFs in skeletal tissue
 Top
 Introduction
 Overview of IGF ligands,...
 IGF-binding proteins (IGFBPs)
 Role of IGFs in...
 Evidence from gene deletion...
 Synthesis and biological actions...
 Interactions among IGFs, GH,...
 Potential therapeutic usages and...
 References
 
Skeletal tissues are rich in IGFs. Baylink et al. found that extracts from demineralized human femora removed during hip replacement procedures contain a factor(s) that stimulates cell division in rat calvaria. The active ingredient that they provisionally called skeletal growth factor was subsequently purified and found on sequence analysis to be IGF-II (33).

The formation of IGFs, their receptors, and their binding proteins in skeletal tissues is regulated by many hormones, including GH, estradiol, testosterone, bone morphogenic proteins, PTH, PTHrP, 1,25-dihydroxyvitamin D3,, and a variety of cytokines and growth factors. At least some of the actions of sex steroids on bone are dependent on their stimulation of IGF production. Estradiol stimulation of cell proliferation and collagen synthesis in rat osteoblasts can be blocked by anti-IGF-I antibodies (34), and testosterone-dependant growth of rat mandibular condyles is also blocked by an antibody to IGF-I (12). In female reproductive tissues, not only is the IGF-I gene responsive to estrogen (35), but, conversely, IGF-I can activate the estrogen receptor in the absence of estrogen (36). There is also cross-talk between the IGF and estrogen signal transduction pathways (37). Such interactions may provide an important key to manipulating IGFs for therapeutic advantage.

The location of IGF production in the epiphyses is pertinent to their role in skeletal growth. Induction of IGF-I messenger ribonucleic acid by GH has been demonstrated in the rodent growth plate, and IGF-I transcripts have been localized to both proliferating and hypertropic chondrocytes. In situ studies, however, suggest minimal expression of IGF-I messenger ribonucleic acid in rodent epiphyses and high expression of the gene encoding IGF-II (11, 38).

It is intriguing to speculate on how abnormal epiphyseal maturation in certain chondrodysplasia might be influenced by the interactions of IGF-I with PTHrP or with fibroblast growth factor (FGF; Fig. 1Go). PTHrP (or PTH) stimulates chondrocyte proliferation at least in part by stimulating increased production of IGF-I; indeed, PTH stimulation of osteoclasts is blocked by an anti-IGF-I antibody (39). The commitment of chondrocytes to further differentiation, however, is inhibited by PTHrP, an action that is opposite that of the IGFs (40). Knockouts of the PTH/PTHrP receptor display accelerated chondrocyte differentiation and disordered organization. Blömstrand chondrodysplasia, a form of short-limbed dwarfism, and Jansen’s metaphyseal chondrodysplasia are both caused by mutated PTHrP receptors in the chondrocyte (41, 42). Thus, a potentially fruitful area for further research is to determine how IGFs influence the effect of PTHrP on chondrocyte differentiation under normal conditions and in the chondrodysplasias resulting from disordered expression of the PTH/PTHrP receptor.



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Figure 1. Many of the chondrodystrophies are the result of mutant genes encoding the receptors for FGF or PTHrP. This figure illustrates that the actions of FGF and PTHrP on the growth plate in these diseases are opposite the actions of IGFs, suggesting possible therapeutic approaches to circumvent the growth impairment in these disorders.

 
Other forms of chondrodystrophies, including achondroplasia, hypochondroplasia, and thanatophoric dysplasia, are caused by gain of function mutations of the FGF receptor (43) that act to decrease chondrocyte proliferation and cellular hypertrophy (44). Studies in growth plate chondrocytes from a fetus with thanotropic dwarfism suggest that the receptor mutation led to premature terminal differentiation and increased apoptosis of chondrocytes in response to FGF (45). The enhanced apoptosis is again opposite the effects of IGF-I. IGF-I inhibits apoptosis in osteoblasts, and survival of these cells is blocked by an IGF-I receptor antibody. It remains to be demonstrated whether the antiapoptotic effects of IGF-I can block the effects of the mutant FGF receptor gene in these hereditary chondrodystrophies (46).


    Interactions among IGFs, GH, and sex steroids in pubertal growth
 Top
 Introduction
 Overview of IGF ligands,...
 IGF-binding proteins (IGFBPs)
 Role of IGFs in...
 Evidence from gene deletion...
 Synthesis and biological actions...
 Interactions among IGFs, GH,...
 Potential therapeutic usages and...
 References
 
The evidence that IGF-I plays a pivotal role in pubertal growth is substantial. In both sexes blood levels of both GH and IGF-I rise dramatically during the second decade, implicating the GH/IGF axis in the pubertal growth spurt (47), and in both sexes, estrogen is the primary stimulus for increased GH secretion and the consequent rise in circulating IGF-I (48). In boys this is presumably accomplished by aromatization of testosterone to estradiol, as nonaromatizable androgens do not exert a GH-priming effect.

There is poor correlation between circulating levels of sex steroids and IGF levels at puberty, possibly due to direct actions of sex steroids on the growth plate. Androgen receptors (49) and both {alpha} and ß estrogen receptors (50) have been localized to human growth plate chondrocytes, and dihydrotestosterone and estradiol have direct actions on human chondrocytes. Another factor contributing to the poor correlation between circulating levels of estradiol and IGF-I may be the biphasic action of estrogen on growth and GH/IGF expression. Low or physiological doses of estrogen augment statural growth (51), whereas the high doses of estrogen used to treat acromegaly or tall stature in girls suppress IGF-I levels and reduce acral and statural growth (52).

New insights on the roles of sex steroids and IGFs in pubertal growth have come from the identification of three rare patients whose epiphyses failed to fuse as the result of disrupted estrogen action. Smith et al. reported a tall, 28-yr-old, normally masculinized man whose epiphyses had not yet fused and who was unresponsive to large doses of exogenous estrogen. His lack of bone maturation was secondary to a loss of function mutation of estrogen receptor {alpha} (53). Two men with p450 aromatase deficiency have been described with a similar phenotype (54, 55). Failure of aromatization caused profound estrogen deficiency and produced skeletal lesions similar to those in the patient with estrogen insensitivity. Treatment of the latter two patients with exogenous estrogens led to epiphyseal fusion and improvement in their skeletal lesions. In all three of these patients the IGF-I levels were appropriate for skeletal age.

These experiments of nature show that estrogen is responsible in both males and females for the terminal phases of epiphyseal differentiation leading to fusion, and that IGF-I is unable to effect epiphyseal fusion in the absence of estrogen. These men, however, were well virilized and attained their midparental height at an appropriate age. Although it is tempting to attribute their estrogen-independent growth during childhood to their normal androgen levels, it is equally possible that their normal growth was attributable to IGF-I. The latter possibility is supported by the relatively normal statural growth of individuals with primary hypogonadism and an intact GH/IGF axis (56). The ability of IGF-I to promote linear growth without unduly accelerating skeletal maturation has important therapeutic implications.


    Potential therapeutic usages and frontiers for further study
 Top
 Introduction
 Overview of IGF ligands,...
 IGF-binding proteins (IGFBPs)
 Role of IGFs in...
 Evidence from gene deletion...
 Synthesis and biological actions...
 Interactions among IGFs, GH,...
 Potential therapeutic usages and...
 References
 
The skeletal disorders that could theoretically be benefited from augmenting or decreasing the actions of IGF-I or IGF-II include various forms of arthritis, glucocorticoid-induced growth arrest, renal osteodystrophies, various chondrodystrophies, healing of fractures, the prevention and treatment of osteoporosis, and many others. Many of the potential uses of IGFs in skeletal disorders have been inferred from therapeutic trials with GH, even though the effects of GH may be quite different from those of IGF-I. GH has a host of direct effects that are catabolic and antiinsulin in nature. These effects are opposite the indirect anabolic effects of GH that are mediated by IGF-I (57). For example, the growth failure that is an invariable feature of high dosage glucocorticoid therapy may be amenable to IGF-I therapy with less chance of glucose intolerance than might be expected from treatment with GH.

The most obvious clinical use for IGF-I is to treat children who are unable to respond to GH itself. The growth responses to IGF-I in these children have been impressive, although not as sustained as those in GH-deficient children treated with GH itself. Underwood et al., who have treated 10 such children for longer than 5 yr, have encountered no serious side-effects, although the children regularly have developed mild enlargement of abdominal viscera and lymphoid tissue (23). Similar findings have not been observed in children treated with GH.

Except in primary IGF-I-deficient states, there are significant disadvantages to the systemic administration of IGF-I or IGF-II for organ-specific purposes. IGF receptors are present in virtually every cell in the body, and exposure to pharmacological concentrations of exogenously administered IGFs are likely to produce unpredictable and unwanted side-effects. Enthusiasm for treating insulin-dependent diabetes, for example, waned when concerns arose that IGF-I might be exacerbating diabetic retinopathy.

Despite the ubiquity of the IGFs and their receptors, the body is able to selectively manipulate the actions of the IGFs by taking advantage of the many layers of regulation that govern their actions. The challenge, therefore, is not only to increase our understanding of the roles that IGFs play under varying pathological circumstances, but to learn how to manipulate these effects in a selective and beneficial manner.

The most obvious approach is to modify access of the appropriate ligand to the target tissue. Because IGF-II is more abundant than IGF-I in blood and skeletal tissue, future studies would profit from comparing the effects of IGF-I and IGF-II with one another and with those of modified forms that do not interact with the IGFBPs.

The six major binding proteins and the proteolytic enzymes that degrade them offer nearly inexhaustible opportunities for selectively modulating the availability of biologically active IGFs to specific targets. A recent example of this approach was a study in transgenic mice in which the smooth muscle hyperplasia induced by selectively overexpressing IGF-I was partially abrogated by concomitantly overexpressing the inhibitory IGFBP-4 (58). Binding proteins might also be manipulated through the hormones that regulate their production and/or degradation or by using modified IGFs that do not attach to binding proteins.

A different approach to capitalizing on the many actions of IGFs in skeletal tissue is to modify the effects of other hormones whose actions are mediated or impacted by IGF. An example is the use of estrogen antagonists that selectively block the effects of estrogen on epiphyseal fusion while retaining their beneficial effects on bone mass. Case reports suggest that tamoxifen, while promoting bone mineralization, may be an estrogen antagonist at the level of the chondrocyte maturation. This is supported by anecdotal reports that tamoxifen treatment can lead to normal statural growth without stimulating bone age advancement in patients with elevated estrogens secondary to McCune-Albright syndrome. In an experimental study, the accelerating effect of estrogen on bone age advancement in mice was blocked by Faslodex, an estrogen receptor blocker (59).

Gene therapy may ultimately prove to be a viable technique for achieving the goals outlined above. Although the enormous potential of gene therapy has proven far more difficult to realize than originally envisioned, it is likely that in coming years we will gain expertise in targeting designer genes to fulfill specific objectives at discrete anatomical sites. To successfully target a modified gene to a specific area or function in the growth plate, it will be important to identify unique promoters or cell-specific fingerprints for the multiple chondrocyte stages in growing bone. Realization of the enormous potential of targeted gene therapy to treat skeletal disorders, however, requires far more knowledge than we now possess on how IGFs function in collaboration with other hormones and growth factors to influence each stage of skeletal growth.

Received August 4, 1999.

Revised September 15, 1999.

Accepted August 12, 1999.


    References
 Top
 Introduction
 Overview of IGF ligands,...
 IGF-binding proteins (IGFBPs)
 Role of IGFs in...
 Evidence from gene deletion...
 Synthesis and biological actions...
 Interactions among IGFs, GH,...
 Potential therapeutic usages and...
 References
 

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