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Endocrinology Vol. 143, No. 10 3711-3714
Copyright © 2002 by The Endocrine Society

ARTICLE

Minireview: Insights from Insulin-Like Growth Factor Binding Protein Transgenic Mice

Josef V. Silha and Liam J. Murphy

Departments of Physiology (J.V.S., L.J.M.) and Internal Medicine (L.J.M.), University of Manitoba, Winnipeg R3E 0W3, Canada

Address all correspondence and requests for reprints to: Liam J. Murphy, M.D., Ph.D., University of Manitoba, Department of Physiology, John Buhler Research Centre, 715 McDermot Avenue, Room 841A, Winnipeg MB R3E 3P4, Canada. E-mail: ljmurph{at}cc.umanitoba.ca.


   Abstract
Top
 Abstract
Introduction
 Future Directions
 References
 
The existence of abundant high affinity binding proteins for the IGFs, the IGF binding proteins (IGFBPs), was first demonstrated more than 40 yr ago in the very early days of somatomedin research. With the development of molecular techniques and transgenic and knockout mouse models, the nature, complexity, and redundancy of the IGFBPs have now started to be elucidated. Indeed the functional role of the circulating IGFs and the originally proposed endocrine somatomedin hypothesis have recently been questioned. The limited reports to date indicate that IGFBP knockout mice have few phenotypic manifestations. In contrast, overexpression of IGFBPs in transgenic mice is associated with manifestations that provide some insight into the physiological role of the binding proteins. The predominant effect of generalized or tissue-specific overexpression of the IGFBPs has been growth inhibition as would be anticipated from inhibition of the actions of IGF-I and -II. In addition, impaired glucose homeostasis and reduced fecundity have been observed in both IGFBP-1- and IGFBP-3-overexpressing transgenic mice. This review examines the data reported to date for transgenic mouse models that overexpress IGFBPs. In addition, data from transgenic mice that overexpress the acid-labile subunit, an important component of the ternary complex, have also been reviewed.


   Introduction
Top
 Abstract
 Introduction
Future Directions
 References
 
THE IGF BINDING PROTEINS (IGFBPs) ARE relatively abundant secreted proteins that have the ability to bind IGF-I and IGF-II with affinities comparable to their respective receptors. They are conserved in lower species, suggesting an important role throughout evolution (1). Functional redundancy within the IGFBP family is suspected because genetic nullification of any one of the IGFBP genes have, at best, modest phenotypic effects in mutant mouse models (2, 3). In addition to their role in the modulation of the mitogenic action of the IGFs, the IGFBPs have been reported to have a variety of diverse functions, including promotion of cell migration, induction of apoptosis, senescence, and differentiation, depending upon the cell type (4), nuclear localization, and interaction with RXR-{alpha} (5). Most of these data have been generated using in vitro culture systems, and it remains to be determined whether any of these actions have physiological significance in vivo.

In vivo studies of IGFBP action have been limited until recently by the lack of large quantities of purified IGFBPs. Some insights into the physiological role of the IGFBPs are now emerging with development of transgenic mouse models where targeted or generalized overexpression have been achieved. Targeted and generalized IGFBP overexpression address different questions. Generalized IGFBP overexpression ensures that both high circulating and tissue levels are achieved and can determine the overall effect of increased binding protein on the whole animal. Targeted IGFBP overexpression allows for the investigation of local effects of IGFBP expression in specific tissues without perturbing circulating levels of IGFBPs, the IGFs, or other components of the IGF system.

The predominant manifestation of IGFBP overexpression has been generalized or localized growth retardation (Table 1Go). Less consistently, effects of IGFBP overexpression on glucose homeostasis and reproductive function have also been reported (6, 7, 8, 9, 10, 11, 12). The reports of overexpression of IGFBPs in transgenic animals have not provided any support for an important physiological role of the IGF-independent effects of the IGFBPs. However, there have as yet been no reports of in vivo experiments that directly test any of the IGF-independent effects of the binding proteins. It is conceivable that subtle IGF-independent effects of the IGFBPs may have been masked or overlooked in the data obtained for transgenic mice overexpressing the binding proteins.


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  		Table 1. Effects of overexpression of IGF binding proteins in transgenic mice

 
Generalized overexpression of IGFBP-3 in transgenic mice is associated with both pre- and postnatal growth retardation (6). The effect is less marked than that observed with IGFBP-1 overexpression (7), but like IGFBP-1 overexpression, IGFBP-3 overexpression is manifested by marked reduction in brain size (6, 7, 12). Modest hyperglycemia, hyperinsulinemia and glucose intolerance is observed in IGFBP-3 transgenic mice (our unpublished observations). A reduction in litter size was also observed in IGFBP-3 Tg mice as had been reported for IGFBP-1 Tg mice (6, 7). Ubiquitous overexpression of IGFBP-2 is also associated with reduced postnatal weight gain (10). This was particularly apparent in double transgenic where GH was also overexpressed (11). In the latter situation, tissue overexpression of IGFBP-2 was able to attenuate the effects of elevated tissue expression of IGF-I.

The increase in circulating IGFBP-3 in transgenic mice was accompanied by an increase in plasma total IGF-I levels of approximately 1.4-fold. The majority of the human IGFBP-3 detected in the plasma from transgenic mice was present as a 150-kDa complex (6). The small fraction of the circulating total IGF-I present as "free" or easily dissociable IGF-I was also increased approximately 1.8-fold in the IGFBP-3 transgenic mice (our unpublished observations). However, it is unclear whether the ultrafiltration technique used to measure "free" IGF-I is valid in the presence of elevated IGFBP-3 levels. The increase in total IGF-I present in the circulation of the IGFBP-3 transgenic mice may result from an increase IGF-I synthesis, decreased IGF-I clearance or a combination of both. Although "free" or easily dissociable IGF-I was also increased, the predominant phenotypic manifestation of IGFBP-3 overexpression appears to one of impaired IGF-I action. Because of the ubiquitous expression of the transgene, the phenotypic effects observed may be the result of local tissue actions of the IGFBP-3 rather than perturbations in circulating IGF levels.

The majority of IGF present in the circulation is tightly bound to IGFBP-3 in ternary complex containing the acid-labile subunit (ALS) (13). The regulation of ALS levels is important in determining circulating IGF levels and may be important in determining efflux of IGF-I and -II from the circulation to tissues (13). The ternary complex appears to act as a relatively stable reservoir of IGF. A smaller fraction of IGF is bound to IGFBP-3 not associated with ALS and to other binding proteins including IGFBP-1. Approximately 1–5% of the total circulating IGF-I is present as free or at least very easily dissociable from the binding proteins. Recent experiments have provided clarification on the source and regulation of the major components of the ternary complex. The ALS is expressed predominantly in the parenchymal liver cells, and its expression is tightly regulated by GH (14). IGFBP-3 is expressed in hepatic nonparenchymal cells as well as endothelial cells. Hepatic expression of IGFBP-3 is also regulated by GH either directly (15) or indirectly via IGF-I production in adjacent hepatocytes (16).

The physiological relevance of the ternary complex IGF reservoir for growth regulation has recently been questioned with the demonstration that normal postnatal growth occurs in mice with conditional nullification of hepatic IGF-I expression (17, 18). However, it is important to note that in these mice induction of the null mutation did not occur until well into the postnatal period and that serum IGF-I levels were probably normal during the early postnatal period of maximal growth velocity. After induction of the liver-specific IGF-I null mutation these mice have low circulating total IGF-I levels although "free" or easily dissociable IGF-I levels appear to be normal (19), and there is no deceleration of growth compared with intact mice. If it is the free rather than the total circulating IGF-I that is important in growth, the question remains as to what function the "bound" IGF-I serves. IGFBP-3 levels are low in the liver IGF knockout mice as expected (18). It would be anticipated that ALS levels may be enhanced because of the higher GH levels observed in these mice (18). Furthermore, although postnatal growth in the liver IGF-I knockout mice is not discernibly different from the intact wild-type mice, it should be noted that these experiments are done under laboratory conditions where mice have ad libitum access to food and where growth may be optimal.

In contrast, the modest growth retardation observed in ALS knockout mice would suggest that the ternary complex is indeed important in postnatal growth (20). ALS serves as a component of IGF system in the circulation where it forms ternary complexes with IGFBP-3 or -5, and IGF-I or -II (13). Association into the ternary complex increases the half-lives of IGFs from approximately 10 min in the free form, to more than 12 h in the ternary complex (21). In this reservoir, rapid egress of the IGFs from the circulation is prevented. Limitation of the acute metabolic effects of the IGFs is the commonly accepted role of the ternary complex. However, this theory has been challenged by the ALS knockout model, in which no obvious metabolic alterations were described. The plasma glucose and insulin levels in ALS knockout mice did not differ from wild-type mice (17).

Hypoglycemia is observed when there are increased levels of free IGFs present in the circulation (22). Nonislet tumor associated hypoglycemia is due to synthesis and secretion of a 15-kDa IGF-II variant. In this condition, elevated levels of big IGF-II are associated with suppressed GH levels and as a consequence, reduced levels of IGF-I, IGFBP-3, and the ALS (22). This results in a decreased proportion of the IGFs present in the ternary complex and presumably increased levels of free IGFs, particularly free IGF-II, in the blood (22). It appears to be the disturbance in the ternary complex formation rather than the level of IGF-II which is important in determining the degree of hypoglycemia (22). An important insight from the IGFBP transgenic mice is that "free" or easily dissociable IGF has a role to play in glucose homeostasis. Impaired glucose tolerance has been observed in several IGFBP-1 overexpressing transgenic mouse lines and also in two different IGFBP-3 transgenic mouse models (Table 1Go). In the latter situation although there appears to be an increase in free or easily dissociable IGF-I the excess IGFBP-3 present in tissues may serve to attenuate the hypoglycemic effect of the excess free IGF-I. IGF-II may be a more potent agonist at the insulin receptor than IGF-I; however, it is virtually absent in the rodent circulation postnatally (23). In humans and other mammals with high concentration of IGF-II in circulation, the sequestration of IGFs into ternary complexes most likely plays a more important role by limiting more potent insulin-like effects of IGF-II. While overexpression of either IGFBP-1 or IGFBP-3 was associated with hyperglycemia, suggesting a role for free or easily dissociable IGF-I in glucose homeostasis, ALS transgenic mice are euglycemic (6, 7, 24).

Immunoreactive ALS, most likely derived from circulation, is also detectable in various body fluids although mostly in very low concentrations (16). Extrahepatic synthesis has been demonstrated in the granulosa and theca cells in the porcine ovary (25). In this context, it is of interest that IGFs are found almost exclusively in 150-kDa complex in human follicular fluid (26) and that ALS overexpressing mice have reduced litter size (24). Some reduction in litter size was observed with IGFBP-3 and IGFBP-1 overexpressing mice (7, 27). However, no reproductive abnormalities have been reported in ALS knockout mice (20).

Mice that overexpress ALS were phenotypically normal at birth and demonstrated a very modest reduction in body weight postnatally (24). Interestingly double transgenic mice with the combination of both ALS and IGFBP-3 overexpression resulted in a more marked reduction in body weight than overexpression of either IGFBP-3 or ALS alone (24). This observation suggests sequestration of IGF-I in the ternary complex may attenuate the growth promoting activity of IGF-I bound to IGFBP-3. This may be physiologically important because under some circumstances binary complexes of IGF-I/IGFBP-3 can have more potent effects than IGF-I alone (28). In transgenic mice that overexpress IGFBP-3 in the mammary gland during lactation, a delay in the involution of the mammary gland after lactation was observed (29). This delay was attributed to potentiation of an IGF-I effect. In the first IGFBP-3 transgenic mice generated in this laboratory where only a very low level of transgene expression was detectable, no discernable effect on postnatal growth was detected (30). However, enlargement of the spleen, liver, and heart was observed (30). It is possible that in vivo as in vitro the relative ratio of IGFBP-3 to IGF-I may be important in determining whether there is inhibition or potentiation of IGF action.


   Future Directions
Top
 Abstract
 Introduction
 Future Directions
References
 
Although we have started to learn more about the role of the IGFBP from transgenic and knockout mice experiments, more questions have been raised than answered by the studies reported to date. The relatively modest effects of the IGFBP knockout mice suggests that more sophisticated experiments and scrutiny for subtle changes will be required to identify the functional role of these binding proteins. Combinatorial elimination of several of the binding proteins through cross-breeding of knockout mice has already begun and has been reported in preliminary form (2). Further transgenic experiments with targeted expression are required. In addition, the endocrine rather than tissue effects of overexpression of the IGFBPs need to be addressed with transgenes using promoter fragments which restrict expression to the organ or cell type that normally expresses the binding protein. For example, IGFBP-3 expression driven by a liver specific promoter is likely to result in high circulating IGFBP-3 levels without the added confounding effects of high tissue expression. To date, most experiments have been carried out under optimal animal husbandry conditions where nutritional and environmental stresses are minimized. Further insights may be gained by examining the existing transgenic and mutant mouse models under conditions that more closely match those observed in nature. For example, differences in growth rates may be observed in food-restricted transgenic or mutant mice and wild-type mice. Finally, overexpression of mutant binding proteins devoid of IGF binding activity may provide insight into the physiological role of the IGF-independent effects observed in vitro.


   Footnotes
 
Abbreviations: ALS, Acid-labile subunit; IGFBP, IGF binding protein.

Received January 30, 2002.

Accepted for publication June 4, 2002.


   References
Top
 Abstract
 Introduction
 Future Directions
 References
 

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