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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 6 1894-1898
Copyright © 1997 by The Endocrine Society

Reproductive Endocrinology

Gestational Age-Dependent Expression of Insulin-Like Growth Factor-Binding Protein-1 (IGFBP-1) Phosphoisoforms in Human Extraembryonic Cavities, Maternal Serum, and Decidua Suggests Decidua as the Primary Source of IGFBP-1 in these Fluids during Early Pregnancy1

N. A. Martina, E. Kim, U. Chitkara, N. C. Wathen, T. Chard and L. C. Giudice

Department of Gynecology and Obstetrics (N.A.M., E.K., U.C., L.C.G.), Stanford University Medical Center, Stanford, California 94305-5317; and Department of Reproductive Physiology (N.C.W., T.C.), St. Bartholomew’s Hospital, London, EC1A 7BE United Kingdom.

Address all correspondence and requests for reprints to: Linda C. Giudice, M.D., Ph.D., Chief, Division Reproductive Endocrinology and Infertility, Department of Gynecology and Obstetrics, Stanford University Medical Center, Room HH-333, Stanford, California 94305-5317. E-mail: giudice{at}stanford.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
The insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are important regulators of fetal and maternal tissue development during pregnancy. Posttranslational modification of IGFBP-1 yields up to six IGFBP-1 phosphovariants and a nonphosphorylated form, which in vitro, have some different properties. Nonphospho IGFBP-1 has less affinity for IGFs than the phospho isoforms and also may have IGF-independent actions. Herein, we have investigated the complement of IGFBP-1 phosphoisoforms present in extraembryonic coelomic (EEC) fluid, amniotic fluid (AF), and maternal serum (MS) throughout human gestation. Also, to determine potential tissue source(s) of IGFBP-1 in these fluids, we have quantified IGFBP-1 and examined IGFBP-1 phosphoisoforms in conditioned media (CM) from maternal decidua, fetal liver, and fetal kidney explants throughout gestation. Western immunodetection revealed that IGFBP-1, present in EEC and AF in early pregnancy and in CM from early pregnancy decidua, is primarily in the nonphosphorylated form. MS in this period contains primarily the nonphospho form and, as in nonpregnant adults, the highly phosphorylated form of IGFBP-1. The phosphorylation profile of IGFBP-1 in AF, MS, and decidua CM changes as pregnancy progresses. All the IGFBP-1 phosphoisoforms ultimately are produced by decidua and are present in midgestation MS, and all but the most highly phosphorylated form are present in AF. In late gestation, MS contains primarily the highly phosphorylated form. In contrast, profiles in CM from explants of fetal liver and kidney at different gestational ages remain unchanged. Nonphosphorylated IGFBP-1 is the primary form in fetal kidney CM, whereas fetal liver CM contains all IGFBP-1 phosphoisoforms. Concentrations of IGFBP-1 in fetal liver and kidney CM are significantly lower (482 ± 146 and 120 ± 32 ng/mL·100 mg wet wt tissue, respectively) than in decidua CM (11,417 ± 2,358 ng/mL·100 mg wet wt tissue). The data cumulatively suggest that maternal decidua is the primary source of IGFBP-1 in EEC, AF, and MS in early pregnancy and that fetal liver and kidney are not likely significant contributors. The presence of nonphospho IGFBP-1 in AF, EEC, and MS suggests an important role for this isoform during early gestation.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
THE INSULIN-LIKE growth factor (IGF) system is comprised of the IGF-I and IGF-II, their binding proteins (IGFBP-1 through -6), IGFBP-proteases, and IGF receptors (1). This growth factor system plays important roles in endometrial cyclic development, blastocyst development, implantation, placentation, and fetal growth and development (1, 2, 3, 4). IGFBP-1, formerly known as placental protein-12, is a major secretory protein and the major IGF-binding protein produced by the endometrium of pregnancy (decidua) (5). Present in low concentration in first trimester amniotic fluid (AF) (6, 7, 8) and maternal serum (MS) in early gestation (8, 9), IGFBP-1 increases rapidly and is abundant in second- and third-trimester AF (8, 9, 10, 11, 12). Extraembryonic coelomic fluid (EEC), lined by the chorion-decidua (Fig. 1Go), is rich in IGFBP-1 in early gestation (9–12 weeks) (8). The relative contributions of fetal and maternal IGFBP-1 to EEC, AF, and MS have not been determined. IGFBP-1 also is a major IGFBP present in fetal circulation (12, 13) and fetal liver (11, 14, 15, 16) and is expressed by fetal kidney (16, 17). Conditioned medium (CM) from fetal liver explants contains IGFBP-1 in greater concentration than any other IGFBP, and fetal kidney produces measurable quantities of IGFBP-1 (16). In contrast to IGFs, IGFBP-1 levels in both fetal and maternal circulations are inversely correlated with birth weight (13, 18, 19, 20). Furthermore, IGFBP-1 has a higher affinity for IGF-I than does the IGF receptor (21, 22, 23). Therefore, a primary action of IGFBP-1 may be to modulate the receptor-mediated cellular activities of IGFs, specifically with respect to fetal and placental growth. IGFBP-1 is an important modulator of IGF activities, and it also has IGF-independent actions. It binds via its RGD sequence to the {alpha}5ß1 integrin on Chinese hamster ovary cells and stimulates their migration (24). IGFBP-1 also binds to human cytotrophoblast {alpha}5ß1 integrin, and invasion into decidua in vitro is inhibited in the presence of IGFBP-1 (25), suggesting a role for IGFBP-1 in the regulation of placental invasion.



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  		Figure 1. Schematic diagram of embryo, placenta, decidua, and extraembryonic cavities in early human gestation.

 
Posttranslational modification of IGFBP-1 may be an important regulator of IGFBP function (26, 27, 28, 29, 30). Highly phosphorylated IGFBP-1 has a higher affinity for IGF peptides than does the nonphosphorylated form (23, 26). Furthermore, nonphosphorylated IGFBP-1 and recombinant IGFBP-1 enhance IGF-mediated actions, whereas the phosphorylated forms do not (23, 27). It has been suggested that, because of their increased ability to sequester IGFs, the phosphoisoforms bind free IGFs and inhibit their cellular actions (26, 27, 28, 29, 30). The role of these forms of IGFBP-1 during human gestation have not been well defined. Different IGFBP-1 phosphoiso-forms are present in MS and AF during human pregnancy (26, 31), and the sources of IGFBP-1 in MS and extraembryonic cavities remains unresolved. Several tissues are candidates, including the maternal decidua, the chorion, the amnion, and the fetal liver and/or kidney via the fetal circulation and passage of fetal urine into the amniotic cavity. Herein, we have characterized the IGFBP-1 phosphoisoforms present in human extraembryonic cavities, MS, and decidua throughout pregnancy and in media conditioned by first- and second-trimester human fetal liver and kidney explants.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Tissues

Human fetal tissues and fluids were obtained from first- and second-trimester elective abortions. Third-trimester decidua was isolated from placentae collected at delivery. Written informed consent was obtained from patients, and protocols were approved by the Stanford University Committee on the Use of Human Subjects in Medical Research and the Ethics Committee of St. Bartholomew’s Hospital, London. Gestational age was calculated based on last menstrual period or sonography. Tissues were obtained immediately and placed in cold DMEM (Mediatech Inc, Herndon, VA) for transport (within 5 min) to the laboratory for further processing. In cases where gestational age was 12 weeks or less, EEC fluid was aspirated first (because of anatomy and accessibility), and then AF was aspirated. Figure 1Go demonstrates the relationship of the extraembryonic cavities, the fetus, the placenta, and the maternal decidua (from (8)). These samples were obtained under transvaginal sonographic guidance using a 5-mHz curvilinear transvaginal probe (Aloka SSD-620, Tokyo, Japan), as described (7, 8). All other AF samples were obtained transabdominally under ultrasound guidance using standard amniocentesis procedures. All fluids were centrifuged for clarification and stored at -20 C until further use.

Explant cultures

Fetal tissues and decidua were washed extensively in DMEM and weighed before mincing into 2-mm3 pieces and cultured in serum free DMEM supplemented with 1% BSA (Sigma Diagnostics, St. Louis, MO) and 10 ug/mL transferrin (Sigma). Cultures received 1 mL of medium per 100 g of tissue. Conditioned media (CM) were harvested after 48 h incubation at 37 C in 9% O2 and were clarified by centrifugation before storing at -20 C until further use.

IGFBP-1 quantification

An immunoradiometric assay (Diagnostic Systems Laboratories, Webster, TX) was used to quantify IGFBP-1 present in EEC, AF, MS, and explant CM. This assay is specific for human IGFBP-1 and has a sensitivity of 1.0 ng/mL. The intraassay coefficients of variation were 0.9% at 4.9 ng/mL and 5.2% at 12.1 ng/nL (n = 12). The interassay coefficients of variation were 1.1% at 5.1 ng/mL and 4.8% at 12.8 ng/mL (n = 6), respectively. All samples were run in the same final assay for the purpose of ANOVA, which was performed using Statview II software (Santa Monica, CA).

Immunoprecipitation

In serum samples, because of the low levels of IGFBP-1 and the abundance of other proteins, it was necessary to immunoprecipitate IGFBP-1 from serum before loading onto gels. Three monoclonal antibodies against human IGFBP-1 were tested for their ability to immunoprecipitate all IGFBP-1 phosphoisoforms from serum. Mouse monoclonal antibodies 6303 and 6305 (32) (Medix Biochemica (Kaunianen, Finland)) were used at 1 ug/mL. A mouse monoclonal from Diagnostic Systems Laboratories was used at 1 or 2 ug/mL. Although all were found to precipitate all the IGFBP-1 phosphoisoforms, the DSL antibody produced the most consistent results overall and thus, was selected for use in this study. An amount of serum containing 5 ng of IGFBP-1 was incubated with antibody in 0.25% BSA with 0.1% Tween 20 (Sigma) in phosphate-buffered saline for 4 h at 4 C in a total vol of 0.5 mL. Antimouse Ig coupled to agarose (Sigma) was then added for 30 min at 25 C to precipitate the antibody-IGFBP-1 complex, which was then washed 3 times in BSA/Tween/phosphate-buffered saline. The resulting pellets were boiled for 5 min in loading buffer consisting of 170 mmol/L TRIS (pH 5.5), 90 mmol/L n-octylglucoside, 40% glycerol, and 0.008% bromophenol blue (all from Sigma) and centrifuged. The supernatant was carefully removed and stored at 4 C overnight before loading onto gels.

Western immunodetection

CM, EEC, AF, or precipitated MS, containing 5 ng of IGFBP-1, were applied to 10% nondenaturing polyacrylamide gels for electrophoresis. Immunodetection of IGFBP-1 was carried out using monoclonal antibody 6303 at 1 ug/mL in 1% BSA/20 mmol/L Tris/150 mmol/L NaCl/0.5% NP40/0.2% Tween 20 for 4 h at room temperature, followed by antimouse-HRP (Amersham, Arlington Hts., IL) and ECL (Amersham). Conditioned medium from HepG2, a human hepatoma cell line, and term AF were included as controls on all gels to ensure that nonphospho and all phosphoisoforms of IGFBP-1 were present and detectable.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Figure 2Go shows the profile of IGFBP-1 isoforms in EEC (n = 16) of early gestation and AF (n = 15) throughout pregnancy, determined by Western immunoblotting. EEC (Fig. 2AGo) contains primarily the nonphospho form of IGFBP-1 and minor amounts of the least phosphorylated form. No other phosphoisoforms were found in EEC. During early pregnancy, the AF profile (Fig. 2BGo) is identical to that in EEC after fusion of the amnion and chorion between 11 and 13 weeks of gestation. However, as gestation progresses, increased amounts of the higher phosphorylated forms of IGFBP-1 are detected. By midgestation, the pattern is identical to that of term AF. The most highly phosphorylated form of IGFBP-1, which is present in HEP-G2-conditioned medium (control), was consistently undetectable in AF, even at term.



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  		Figure 2. IGFBP-1 phosphorylation profiles in extraembryonic coelom (A) and AF (B), determined by Western immunoblotting. Gestational ages (weeks+days) are shown at the bottom of each panel. Also shown are HEP-G2-conditioned medium (lane 9, both panels) and term AF treated with alkaline phosphatase (lane 10, both panels). Term AF is in lane 8, panel A. Data in panel A are representative of samples (n = 16) between 9 and 12 weeks of gestation. Data in panel B are representative of samples (n = 2) of 10- to 11-week AF, samples (n = 7) of 16- to 24-week AF, and samples (n = 6) of 33- to 38-week AF.

 
The IGFBP-1 phosphoisoforms in MS (Fig. 3Go) are strikingly different from EEC or AF throughout gestation. All MS samples contained the highly phosphorylated form throughout pregnancy. MS samples collected in the first trimester (n = 6) displayed primarily the nonphosphorylated form of IGFBP-1, in addition to the highly phosphorylated form. In samples collected in the second trimester (n = 7) and early third trimester (n = 4), all the phosphoisoforms are present, and the nonphosphorylated form no longer codominates with the highly phosphorylated form, as observed in the first trimester. In late gestation (n = 8), primarily the highly phosphorylated form is present, similar to nonpregnant serum (31).



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  		Figure 3. IGFBP-1 phosphorylation profiles in MS from first (lanes 1–3), second (lanes 4–6), and third (lanes 6–9) trimester, as determined by Western immunoblotting. For comparison, HEP-G2-conditioned medium (lane 10) and AF treated with alkaline phosphatase (lane 11) are shown. Data shown are representative of samples for first (n = 6), second (n = 7), and third (n = 8) trimesters, respectively.

 
In an effort to determine the potential source(s) of nonphosphorylated IGFBP-1 present in EEC, AF, and MS, maternal decidua and first- and second-trimester fetal kidney and liver were collected and cultured as explants for 48 h. Conditioned medium (CM) was collected, and IGFBP-1 was measured by immunoradiometric assay (Table 1Go) and analyzed for IGFBP-1 phosphoisoforms by Western immunoblotting (representative samples in Figs. 4Go and 5Go). This method has the drawback of not distinguishing among synthesis, secretion, and release of stored intracellular IGFBP-1, which may influence the outcome of the results. The concentration of IGFBP-1 in CM from maternal decidua was 93-fold greater than in fetal kidney CM and 23-fold more than fetal liver CM. In a pattern very similar to AF, CM from decidua explants (Fig. 4Go) contained primarily the nonphospho form until midgestation, at which time the more highly phosphorylated forms began to appear. However, in contrast to AF, the most highly phosphorylated form of IGFBP-1, which is present in HepG2-conditioned medium, also is present in decidua explant CM by midgestation. Fetal kidney explant CM (Fig. 5Go) contained exclusively the nonphospho and least phosphorylated forms throughout the first and second trimesters, whereas fetal liver CM contained all the phosphoisoforms, similar to HepG2 CM.


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  		Table 1. Concentrations of IGFBP-1 in explant conditioned media

 


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  		Figure 4. Western immunoblot of IGFBP-1 phosphoisoforms present in conditioned medium from decidua explants collected throughout gestation. Gestational age (in weeks) is indicated at the bottom. Lanes 9 and 10 contain AF treated with alkaline phosphatase and HEP-G2-conditioned medium, respectively. Data shown are representative of samples (n = 8) from first trimester decidua, samples (n = 7) from second trimester decidua, and samples (n = 6) from third trimester decidua.

 


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  		Figure 5. IGFBP-1 phosphoisoforms present in conditioned medium from fetal kidney (A) and fetal liver (B) explants. Gestational ages (in weeks) are indicated at the bottom. These data are representative of 14 fetal kidney samples (n = 2 at 11 weeks and n = 12 between 14 and 21 weeks) and 10 fetal liver samples between 13 and 21 weeks. AF treated with alkaline phosphatase is shown in lane 6, panel A and lane 5, panel B. HEP-G2-conditioned medium is shown in lane 5, panel A and lane 6, panel B.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study has examined IGFBP-1 phosphorylation profiles in EEC of early human gestation, in AF and MS throughout gestation, and in conditioned medium from explant cultures of maternal decidua and fetal liver and kidney. Nonphosphorylated IGFBP-1 is the predominant form in early gestation maternal decidua and extraembryonic cavities. It is more predominant in early- vs. late-gestation MS. The data cumulatively suggest that the maternal decidua is the source of nonphospho IGFBP-1 in these fluids in early gestation. As gestation progresses, all the phosphoisoforms are observed in decidua CM, and all but the most highly phosphorylated form can be detected in AF, as previously reported (26). In addition, in agreement with Westwood et al. (31), we find that all the IGFBP-1 phosphoisoforms are increased in MS during midgestation and that highly phosphorylated IGFBP-1 is present in MS throughout pregnancy. Given that media conditioned by decidua contains all of these forms by midgestation, it is likely that decidua also is the source of increasing amounts of IGFBP-1 found in AF and in MS during the second trimester of pregnancy. However, it is unclear why all the IGFBP-1 phosphoisoforms are not found in the maternal circulation at term and why the most highly phosphorylated IGFBP-1 isoform in decidual explant CM is not observed at any gestational age in AF.

The presence of highly phosphorylated IGFBP-1 in MS seems unchanged throughout gestation, although accurate changes in this isoform await reliable quantitation methods that currently are not available. A recent study has shown that the highly phosphorylated IGFBP-1 found in the circulation of nonpregnant individuals can be upregulated by insulin, glucagon, combined oral contraceptives, somatostatin, and IGF-I, although the other phosphoisoforms could not be induced under these conditions (33). Similar regulation in pregnancy awaits further investigation.

Although several studies have demonstrated the presence in and secretion of IGFBP-1 by fetal liver and kidney (11, 14, 16), this is the first study to look at IGFBP-1 phosphoisoforms in media conditioned by these tissues. Unlike the temporal differences of IGFBP-1 phosphoisoforms in maternal circulation, AF, and CM from decidua, media conditioned by fetal liver and kidney contained consistent phosphorylation profiles throughout the gestational period studied. Furthermore, the phosphorylation patterns were tissue-specific, with CM from fetal liver containing all the phosphoisoforms, whereas fetal kidney CM had primarily the nonphosphorylated form. IGFBP-1 present in AF and EEC in early gestation are unlikely to be of fetal origin, because excretion of fetal waste products do not appear in AF until the middle of the second trimester (34), and the amount of IGFBP-1 present in fetal kidney explant CM is nearly 2 orders of magnitude lower than levels in decidual explant CM and several orders of magnitude lower than in AF. The data cumulatively support a model whereby decidua secretes IGFBP-1, which diffuses across the chorion into the EEC and (when the EEC is obliterated upon fusion of the chorion and amnion at about 12 weeks of gestation) IGFBP-1 from the decidua reaches the AF. Although immunoreactive IGFBP-1 has been detected in the chorion and amnion (35), recent in situ hybridization studies suggest that IGFBP-1 mRNA is not expressed by these compartments (36), suggesting that they are unlikely contributors of IGFBP-1 in AF.

During the process of implantation and placental invasion, which continues until about the middle of the second trimester, the invading trophoblast encounters an IGFBP-1-rich environment within the decidua. Given that IGFBP-1 binds to {alpha}5ß1 via its RGD sequence (24) and that IGFBP-1 inhibits trophoblast invasion into decidual multilayers in vitro (25), IGFBP-1 may be an important modulator of placental invasion. Our findings that nonphosphorylated IGFBP-1 is abundantly found in media conditioned by decidua during the time of aggressive trophoblast invasion, and that this is the primary form at this time, are suggestive that nonphospho IGFBP-1 plays an important role in regulating early trophoblast invasion into decidua. In addition to the putative role of nonphosphorylated IGFBP-1 in regulating trophoblast invasion, phosphorylated IGFBP-1 may regulate the activities of IGFs on placental function and in meeting the increasing demands of the fetus for growth and development during the later stages of pregnancy. Although this is an attractive hypothesis, functional differences in IGFBP-1 phosphoisoforms in pregnancy await further elucidation.


   Footnotes
 
1 This work was supported, in part, by NIH Grant HD-25220–06 (to L.C.G.). Back

Received September 26, 1996.

Revised January 28, 1997.

Accepted February 19, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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H. Honkanen, E.-M. Rutanen, and O. Heikinheimo
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M. Westwood, J. D. Aplin, I. A. Collinge, A. Gill, A. White, and J. M. Gibson
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S. Sheikh, P. Satoskar, and D. Bhartiya
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