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Reduction of the Disintegrin and Metalloprotease ADAM12 in Preeclampsia

From the Department of Clinical Biochemistry, Statens Serum Institut, Copenhagen; Institute of Molecular Pathology, University of Copenhagen; Department of Gynecology and Obstetrics, Rigshospitalet, University of Copenhagen; and Department of Gynecology and Obstetrics, Hvidovre University Hospital, Copenhagen, Denmark.

	ABSTRACT

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Objectives: The secreted form of ADAM12 is a metalloprotease that may be involved in placental and fetal growth. We examined whether the concentration of ADAM12 in first-trimester maternal serum could be used as a marker for preeclampsia.

Methods: We developed a semiautomated, time-resolved, immunofluorometric assay for the quantification of ADAM12 in serum. The assay detected ADAM12 in a range of 78–1248 µg/L. Serum samples derived from women in the first trimester of a normal pregnancy (n = 324) and from women who later developed preeclampsia during pregnancy (n = 160) were obtained from the First Trimester Copenhagen Study. ADAM12 levels were assayed in these serum samples. Serum levels of ADAM12 were converted to multiples of the median (MoM) after log-linear regression of concentration versus gestational age.

Results: Serum ADAM12 levels in women who developed preeclampsia during pregnancy had a mean log MoM of –0.066, which was significantly lower than the mean log MoM of –0.001 for ADAM12 levels observed in serum samples from women with normal pregnancy (P = .008). The mean log MoM was even lower in serum derived from preeclamptic women whose infant's weight at birth was less than 2,500 g (n = 27, mean log MoM of –0.120, P = .053).

Conclusion: The maternal serum levels of ADAM12 are significantly lower during the first trimester in women who later develop preeclampsia during pregnancy when compared with levels in women with normal pregnancies. Because the secreted form of ADAM12 cleaves insulin-like growth factor binding protein (IGFBP)-3 and IGFBP-5, the IGF axis may play a role in preeclampsia. ADAM12 may be a useful early marker for preeclampsia.

Level of Evidence: II-2

The ADAM (A Disintegrin And Metalloprotease) proteins constitute a multidomain glycoprotein family with proteolytic and cell-adhesion activities.² Human ADAM12 exists in 2 forms: ADAM12-L (long) and ADAM12-S (short). ADAM12-S is the secreted form of ADAM12. ADAM12-S differs from ADAM12-L at the carboxyl-terminus, in that it does not contain transmembrane or cytoplasmic domains. The mRNA species for ADAM12-L and ADAM12-S are abundant in placenta,³ and ADAM12-S is present in gestational serum^6,7 starting early during the first trimester and increasing through pregnancy.⁸ ADAM12-S binds to and has proteolytic activity against IGFBP-3 and, to a lesser extent, IGFBP-5.^6,7 In vitro, ADAM12 cleaves the 44-kDa IGFBP-3 into several fragments of 10–20 kDa,⁶ in a manner that is independent of IGF-I and IGF-II.⁶ It can be hypothesized that the proteolysis of IGFBP-3 stimulates growth by increasing levels of bioavailable IGF-I and IGF-II.^6,9 Langford et al¹⁰ showed that levels of IGFBP-3 protease activity were elevated in the serum of women in the third trimester of pregnancies with uteroplacental insufficiency. Furthermore, it has been suggested that reductions in pregnancy associated plasma protein A (PAPP-A), another placenta-derived IGFBP-4 and -5 protease, may serve as a predictor of intrauterine growth restriction.^11,12 Thus, ADAM12 is an interesting candidate marker for pregnancy complications. We have recently demonstrated that ADAM12 is reduced in maternal serum of pregnancies with chromosomal abnormalities.^8,13 In the present study, we developed a semiautomated, time-resolved, immunofluorometric assay to quantify ADAM12 in serum and used it to assess ADAM12 levels in first-trimester maternal serum as a potential marker for preeclampsia.

	MATERIALS AND METHODS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Serum samples from 484 pregnant women in weeks 10–14 of pregnancy were obtained from the First Trimester Copenhagen Study, through Copenhagen University Hospital of Hvidovre and Rigshospitalet, Denmark, and Statens Serum Institut, Denmark. The study enrollment period was from 1997 to 2001.¹⁴ Gestational age was determined by crown-rump length. All routine samples were taken in dry containers and were kept in cool storage (4°C) for a maximum of 48 hours until postage via the normal mail (duration of dispatch 1–2 days). The samples underwent 2 freeze-thaw cycles (range 2–4) before ADAM12 measurement. ADAM12 is stable for 4 days at 4°C, for 5 hours at room temp, and for at least 7 freeze-thaw cycles.⁸ Of the original 9,941 women in the First Trimester Copenhagen Study, 6,441 had serum samples taken, and of these we retrieved 160 from preeclamptic pregnancies. All records that could be retrieved from women who had been diagnosed with preeclampsia were checked. However, only those women for whom the criteria were documented and serum samples had been taken and could be retrieved were included. Therefore, the specimens used were all the samples complying with the inclusion criteria. Inclusion criteria were systolic resting blood pressure more than 140 mm Hg and diastolic blood pressure more than 90 mm Hg in a previously normotensive woman and proteinuria exceeding 0.5 g/24 hours. A diastolic rise in blood pressure exceeding 20 mm Hg during pregnancy and proteinuria exceeding 0.3 g/24 hours were also criteria for preeclampsia, but no women in the First Trimester Copenhagen Study were found to meet these criteria, and they are no longer used as qualifying criteria for preeclampsia according to the guidelines of the Danish Society for Obstetrics and Gynecology (http://www.dsog.dk).

Blood pressure was measured after a minimum of 5 minutes rest with the woman in a half-sitting or sitting position, with the brachium at heart level. Severe preeclampsia was diagnosed when diastolic blood pressure exceeded 110 mm Hg and/or subjective symptoms/abnormal laboratory findings were present. The subjective symptoms and abnormal laboratory findings were as follows: central nervous system—headache, blurred vision, and cramps (eclampsia); circulation—lung stasis and lung edema; liver—epigastric pain, severely raised liver enzymes (aspartate aminotransferase/alanine aminotransferase > 100 U/L), and raised s-bilirubin; kidneys—oligouria less than 400 mL/24 hours, severe proteinuria more than 3 g/24 hours, serum urate more than 45 mmol/L, and serum creatinine more than 110 mmol/L; coagulation—thrombocytes less than 100 x 10⁹/L, disseminated intravascular coagulation, hemolysis (lactate dehydrogenase > 1,000 U/L and or haptoglobin < 1 µmol/L), activated partial thromboplastin time more than 1.5 x starting value, antithrombin III less than 70, and D-dimer more than 2 mg/L; and hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome, all according to the guidelines of the Danish Society for Obstetrics and Gynecology (http://www.dsog.dk). Two subgroups were separately investigated. The first subgroup included patients with severe preeclampsia (systolic blood pressure > 160 mm Hg and diastolic blood pressure > 110 mm Hg, or a rise in blood pressure during pregnancy exceeding 30 mm Hg and proteinuria exceeding 0.5 g/24 hours) (n = 37). The second subgroup included women with preeclampsia who gave birth to babies with birth weights less than 2,500 g (n = 27). Eight women met the requirements for both subgroups. Control samples included 324 serum samples from the First Trimester Copenhagen Study from women with uncomplicated pregnancies matched for maternal age, parity, and gestational age. All included samples were from singleton pregnancies.

All samples were collected for the Copenhagen First Trimester Study and approved by the Scientific Ethics Committee of Copenhagen and Frederiksberg Counties. Recombinant human ADAM12-S was used for standardization as described.⁸ Protein concentration was determined with the BCA Protein Assay Kit (Pierce, Rockford, IL). Monoclonal antibodies 6E6 and 8F8^3,15 were used for the coating and detection steps, respectively, of the ADAM12 immunofluorometric assay.⁸

Biotinylated 8F8 monoclonal antibody was produced as previously described.⁸ Briefly, 8F8 immunoglobulin G was transferred to a labeling buffer consisting of 0.1 mol/L NaHCO₃ (pH 8.2; Merck, Darmstadt, Germany) by using NAP-5 columns (Amersham Biosciences, Uppsala, Sweden). Biotin (Sigma, Steinheim, Germany), dissolved at a concentration of 40 mg/mL in dimethylformamide (LabScan, Valby, Denmark), was added to the antibody (10 µL biotin solution per milligram of antibody). After mixing at room temperature for 2 hours, biotinylated antibodies were purified by gel filtration using PD-10 columns (Amersham Biosciences).

Three ADAM12 solutions (161 µg/L, 319 µg/L, and 714 µg/L) were prepared from a second-trimester serum pool diluted in Multibuffer (Perkin Elmer, Turku, Finland) to use as controls. We calibrated a third-trimester serum pool against recombinant ADAM12 and used the pool to generate a standard curve to determine ADAM12 concentrations. Five standards, ranging from 78 to 1,248 µg/L, were prepared by diluting the serum in Multibuffer. All standards, controls, and samples were analyzed in duplicate, and all ADAM12 quantifications were done without knowledge of the diagnosis.

Microtiter plates (Nunc-Immuno Plate, MaxiSorp Surface; Nalge Nunc International, Rolkilde, Denmark) were coated with the monoclonal antibody 6E6 (0.50 µg/well) in 0.1 mol/L carbonate buffer (pH 9.6). Plates were incubated overnight at 4°C and then washed twice with washing buffer (Delfia Wash Solution; PBS-Wallac, Turku, Finland). Drying buffer (15 g/L bovine serum albumin; Sigma, Steinheim, Germany; and 25 g/L sucrose dissolved in phosphate-buffered saline) was then added to each well (150 µL/well). The plates were then incubated for 1 hour at room temperature, aspirated, dried at 4°C, sealed, and stored at 4°C.

The Autodelfia (Perkin Elmer, Turku, Finland) was programmed to perform the following steps: prewash the coated plates and dispense 50 µL Multibuffer per well; dispense standards and controls diluted in Multibuffer; add 50 µL of samples (diluted in Multibuffer, if necessary); incubate for 2 hours at room temperature, followed by 4 washes; dispense biotinylated monoclonal antibody 8F8 diluted to 7 µg/mL in Multibuffer; incubate 1 hour at room temperature, followed by 4 washes; dispense europium-labeled streptavidin (0.1 mg/mL; DAKO, Glostrup, Denmark) diluted in Multibuffer to 0.1 v/v (100 µL/well); incubate 1 hour at room temperature, followed by 3 washes; dispense 200 µL of enhancement solution; and count immunofluorescence units after 10 minutes as described for the Autodelfia system.¹⁶

To determine the value of ADAM12 maternal serum concentration as a screening marker for preeclampsia, we analyzed first-trimester maternal serum samples from pregnancies with confirmed preeclampsia. We then compared the values with the regressed median value for maternal serum ADAM12 concentrations from normal pregnancies at the same gestational age. We also compared the normal serum values with the value of severe preeclamptic samples and the samples from preeclamptic pregnancies with birth weight less than 2,500 g.

Median serum ADAM12 concentrations were estimated as the antilogarithm₁₀ to the means of ADAM12 concentrations obtained by linear regression of the logarithm₁₀ ADAM12 concentration by gestational age (days) of the unaffected pregnant women. All concentrations were transformed into multiples of the calculated medians (MoMs) of unaffected pregnant women to obtain gestational age-independent concentration values. Compatibility with the normal distribution was ascertained with normal probability plots. Residuals were normally distributed. The log MoM values of the unaffected women were then compared to those of the affected women by using a 2-sample t test.

	RESULTS

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
Quantitation of ADAM12 was performed with a semiautomated, time-resolved, immunofluorometric assay (Autodelfia). The dilution curves of the recombinant ADAM12 standard and the pregnancy serum standard were parallel. The mean recovery of concentrated ADAM12 added to serum samples was 113% (range 106–120%, n = 3). The dilution curves were linear in the concentration range from 119 µg/L to 356 µg/L, with a correlation coefficient of 0.91–1.00. Intra-assay variation was determined to be 5.6%. The average intra-assay variations for 5 different concentrations in 8 runs were from 3.5% to 7.8%. Determining ADAM12 concentration by Autodelfia (n = 125) and by the previously described enzyme-linked immunosorbent assay (ELISA) method (n = 6)⁸ on 3 controls in the low, median, and high area of the assay range, respectively, showed the difference in the mean value from the 2 assays to be highly consistent (4–11%).

These results suggest that the new immunofluorometric assay is a reliable method for quantifying ADAM12 levels in serum samples. Using this assay, we determined ADAM12 levels in the serum of women in the first trimester of normal pregnancy (n = 324) and women in the first trimester of pregnancy who later developed preeclampsia (n = 160) (Table 1). Figure 1 shows the serum ADAM12 values in these 2 populations.

View larger version (18K): [in this window] [in a new window]   Fig. 1. Serum ADAM12 as a function of gestational age. Control, x; preeclampsia, o. Upper and lower tendency lines are for control and preeclampsia populations, respectively. Laigaard. ADAM12 and Preeclampsia. Obstet Gynecol 2005.

Overall, the first-trimester maternal serum concentrations of ADAM12 in women who later developed preeclampsia (n = 160) had a mean value of 398 µg/L (median 365 µg/L), and the controls (n = 324) had a mean value of 463 µg/L (median 396 µg/L). In both cases the mean and median gestational ages were 90 and 91 days, respectively. The first-trimester maternal serum concentrations of ADAM12 in women who later developed preeclampsia had a mean log MoM of –0.066 (standard deviation [SD] 0.258, range –1.009 to 0.441). This value was significantly lower than the ADAM12 concentration in normal pregnancies, which had a mean log MoM of –0.001 (SD 0.239, range –1.071 to 0.508) (P = .008). The corresponding log MoM medians were 0.009 for controls and –0.035 for the preeclamptic samples.

We subsequently examined 2 subgroups of these patients: those with severe preeclampsia (n = 37) and those who delivered babies with a birth weight less than 2,500 g (n = 27). The rather small number of samples from women who developed severe preeclampsia (n = 37) had a mean log MoM of –0.028 (SD 0.252, range –0.953 to 0.397), which was not significantly different from control levels (P = .533). Interestingly, preeclamptic samples with birth weight less than 2,500 g (n = 27) had a mean log MoM of –0.120 (SD 0.297, range –0.953 to 0.389), and this difference approached statistical significance, as compared with normal samples, despite the low number of samples (P = .053). The distribution of MoM values is shown in Figure 2.

View larger version (15K): [in this window] [in a new window]   Fig. 2. Box-and-whisker plot of multiples of the median (MoM) ADAM12 values in matched controls (n = 324), preeclamptic women (n = 160), severely preeclamptic women (n = 37), and women with pregnancies with birth weight less than 2,500 g (n = 27). Asterisks denote outliers (higher or lower than 1.5 x the interquartile range). The box represents the central 50th percentile interval, and the center line marks the median. The whiskers mark the range of observed values within a distance of 1.5 x the interquartile ranges from the upper and lower limits of the central 50th percentile interval. Laigaard. ADAM12 and Preeclampsia. Obstet Gynecol 2005.

	DISCUSSION

TOP ABSTRACT MATERIALS AND METHODS RESULTS DISCUSSION REFERENCES

 
We have developed a semiautomated, immunofluorometric ADAM12 assay for the Autodelfia platform and used it to determine the concentrations of ADAM12 in 160 serum samples from women in their first trimester of pregnancy who later developed preeclampsia. The concentration of ADAM12 was significantly reduced in these serum samples as compared with sera derived from 324 uncomplicated pregnancies. These findings suggest that ADAM12 might be a valuable marker for preeclampsia. It is very likely that the difference in MoM values is not constant throughout gestation, and a more optimal time for testing ADAM12 as a screening marker for preeclampsia can probably be found. We had earlier found a greater than 60-fold increase in serum ADAM12 values of normal pregnancies from week 8 (180 µg/L) to term (12,000 µg/L). The controls in the present study had a median of 396 µg/L, which is in accordance with our previous finding of a median of 383 µg/L and 450 µg/L at 10 weeks and 11 weeks gestation, respectively, using the ELISA assay.⁸

Only a minority of preeclamptic cases progresses to such an extent that the maternal or fetal health is threatened. Any improvement in early identification of these cases would have a major clinical impact. The 2 subgroups of patients in our study with severe preeclampsia (n = 37) and those who delivered babies with a birth weight less than 2,500 g (n = 27) were relatively small. Nevertheless, we found that serum samples from pregnancies with low birth weight had the lowest levels in absolute amounts among the preeclamptic patients and that the difference approached statistical significance (P = .053). However, it should be noted that the low birth weight group had a shorter median gestational length at birth (248 ± 27 days [average ± SD], range 167–273) than the severe preeclampsia group (268 ± 30 days [average ± SD], range 167–295). We do not know what proportion of these babies was delivered prematurely because of the threat to the mother's health and what proportion was small for gestational date because of intrauterine starvation. Thus, further investigations, encompassing a larger number of pregnancies, at different gestational ages and with knowledge of other risk parameters, eg, socioeconomic status and smoking and previous obstetric history, will be necessary to determine whether ADAM12 can serve as a robust clinical marker of preeclampsia. A future screening approach is likely to consider risk factors like genetic predisposition and previous preeclampsia and to combine different serum markers, such as PAPP-A, inhibin, and ADAM12 with Doppler ultrasonography to reach a positive predictive value with a sufficiently small false positive rate so as to be of clinical relevance. The new semiautomated immunofluorometric ADAM12 assay for the Autodelfia platform has the advantage of shorter handling time than the previously described ELISA method⁸ and will make it possible to screen large cohorts in a short time.

The etiology of preeclampsia is considered to be multifactorial and remains elusive, despite extensive research.^17,18 Suboptimal placentation, genetic predisposition, immunological maladaptation to pregnancy, and preexisting vascular diseases are all likely to be involved.^17,18 It is tempting to suggest that ADAM12 with its different cellular activities⁵ could play an important role in the growth and function of placenta. However, the underlying mechanism is unknown. Both the membrane-bound form of ADAM12, ADAM12-L, and the secreted form, ADAM12-S, are highly expressed in placenta³ and are produced by trophoblasts.^6,19 It has previously been demonstrated that ADAM12 binds to adhesion receptors, such as integrins and syndecans,²⁰ thereby influencing cell differentiation and cell survival.²¹ Placenta from preeclamptic patients exhibits a different profile of adhesion molecules, ie, integrins, as compared with normal placenta.²² Importantly, these cells fail to adapt their adhesion phenotype from one that is characteristic of trophoblastic cells to one characteristic of endothelial cells.²² It is possible that a reduced amount ADAM12 produced by the trophoblasts in preeclampsia may retard the differentiation pathways between these specific cell types.

Another possible mechanism by which ADAM12 might influence placental growth is through its protease activities. ADAM12-S is an active metalloprotease that can degrade IGFBP-3 and IGFBP-5⁶ and various extracellular matrix molecules, including fibronectin.²² As a sheddase, ADAM12-L can activate heparin-binding-epidermal growth factor,²³ placental leucine aminopeptidase,¹⁹ and possibly other growth factors. One hypothesis is that, through proteolysis of IGFBP-3, ADAM12-S abrogates the binding of IGFBP-3 to IGF-I and IGF-II and inhibits the growth-inhibitory effects of IGFBP-3 itself, thereby stimulating growth. This is consistent with the finding that the effect of structural alteration of IGFBP-3 by proteases results in decreased affinity for the IGFs and an increase in the level of measurable IGF-I in its free form in the circulation.²³ Furthermore, the growth of cultured chick embryo fibroblasts is stimulated more strongly by serum from pregnant women than by serum from women who are not pregnant, although both contain the same amount of measurable immunoreactive IGF-I and-II, and this stimulation is impeded by adding recombinant human IGFBP-3.⁹

We conclude that ADAM12 is a potentially important marker of preeclampsia as well as the earlier demonstrated fetal karyotype abnormalities.^8,13 Additional studies are underway to assess the clinical utility of ADAM12 in large-scale prospective clinical studies.

	Footnotes

 
This study was supported by the Faculty of Health Sciences, University of Copenhagen (J.L.).

The authors thank Lone Rabøl and Jacqueline Tybjerg for their technical assistance.

Address reprint requests to: Ulla M. Wewer, MD, DMSci, Institute of Molecular Pathology, University of Copenhagen, Frederik V's vej 11, 2100 Copenhagen, Denmark; e-mail: ullaw{at}pai.ku.dk.

doi:10.1097/01.AOG.0000165829.65319.65

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Laigaard, J. Articles by Wewer, U. M. Search for Related Content PubMed PubMed Citation Articles by Laigaard, J. Articles by Wewer, U. M. Related Collections General gynecology General obstetrics Gynecologic oncology Maternal/fetal physiology Medical complications of pregnancy Obstetric complications of pregnancy Pediatrics/neonatology Placenta Prenatal Diagnosis Preterm labor