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Amino-Terminal Propeptide of C-Type Natriuretic Peptide and Linear Growth in Children: Effects of Puberty, Testosterone, and Growth Hormone

Division of Endocrinology (R.C.O., J.C.H., N.M.), Nemours Children’s Clinic, Jacksonville, Florida 32207; Department of Medicine (T.C.R.P., T.G.Y., E.A.E.), Christchurch School of Medicine and Health Sciences, Christchurch 8140, New Zealand; and Unit on Growth and Obesity (J.C.H.), National Institute of Child Health and Human Development, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Robert C. Olney, M.D., Division of Pediatric Endocrinology, Nemours Children’s Clinic-Jacksonville, Jacksonville, Florida 32207. E-mail: rolney{at}nemours.org.

	Abstract

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Context: C-type natriuretic peptide (CNP), a paracrine factor of the growth plate, plays a key role in stimulating bone growth. The amino-terminal propeptide of CNP (NTproCNP) is produced in equimolar amounts with CNP and is measurable in plasma, providing a potential biomarker for growth plate activity and, hence, linear growth.

Objective: We explored the effects of puberty, testosterone, and GH treatment on NTproCNP levels in normal and short-statured children.

Design: This was a retrospective analysis of samples obtained during previous studies.

Setting: The study was conducted at a pediatric clinical research center.

Subjects: Children with short stature due to GH deficiency, idiopathic short stature (ISS), or constitutional delay of growth and maturation (CDGM) were studied (n = 37). A cohort of normal-statured adolescent boys was also studied (n = 23).

Interventions: Children with GH deficiency and ISS were studied before and during testosterone and/or GH treatment. Boys with CDGM and healthy controls were studied once.

Main Outcome Measures: The main outcomes were NTproCNP levels before and during growth-promoting therapy and during pubertal growth.

Results: Children with short stature due to GH deficiency, ISS, or CDGM had comparable baseline levels of NTproCNP, and levels increased markedly in response to GH or testosterone treatment. In boys with CDGM, levels were comparable with height-matched controls but were less than those from age-matched controls. In healthy boys, NTproCNP appears to peak with the pubertal growth spurt.

Conclusions: NTproCNP levels increase during growth-promoting therapy and are increased during puberty in boys. This novel biomarker of growth may have clinical utility in the evaluation of children with short stature and for monitoring growth-promoting therapy.

	Introduction

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C-TYPE NATRIURETIC PEPTIDE (CNP) is a small paracrine growth factor that plays an important role in regulating linear growth (reviewed in Ref. 1). It is produced in the growth plate (1, 2), and although expressed in a variety of tissues (2, 3, 4), the primary phenotype of mice lacking CNP, or its receptor natriuretic peptide receptor-B, is dwarfism (2, 5). Similarly, homozygous mutations in the natriuretic peptide receptor-B gene in humans cause acromesomelic dysplasia, Maroteaux type (OMIM no. 60275) (6), a syndrome of severe short-limbed dwarfism in which only the skeleton is affected. In vitro studies confirm that CNP potently stimulates growth plate chondrocyte matrix synthesis and differentiation (7, 8, 9).

CNP is synthesized as a precursor protein that undergoes proteolytic processing before release from the cell (10). The amino-terminal propeptide of CNP (NTproCNP) is a cleavage product of proCNP (11) and is produced in equimolar amounts with CNP. Whereas a variety of clearance pathways limit CNP levels in blood, NTproCNP is easily measured (11). Hence, the level of NTproCNP in blood likely reflects the rate of CNP biosynthesis.

Because CNP is produced in the growth plate as a paracrine factor (1) and its primary role is to regulate growth, we proposed that the blood level of NTproCNP is a direct biomarker of growth plate activity. Because linear growth is the result of growth plate activity, we predicted that NTproCNP levels would correlate with linear growth velocity. This has now been shown in lambs and a heterogeneous group of children (12). Furthermore, in lambs, high-dose dexamethasone (12) or caloric deprivation (13) caused a drop in metacarpal growth velocity and was associated with a marked drop in NTproCNP levels.

The purpose of this study was to explore further the relationship between NTproCNP levels and growth in children. This was a retrospective analysis of samples obtained during three previous studies that involved children with short stature. Children with short stature due to GH deficiency, idiopathic short stature, and constitutional delay of growth and maturation (CDGM) along with a cohort of healthy prepubertal and adolescent boys were examined.

	Materials and Methods

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The subjects for this study participated in one of three studies, all of which have been previously reported (14, 15, 16). All the studies were reviewed by the Nemours Clinical Research Review Committee and the Wolfson Children’s Hospital Institutional Review Committee. Informed consent was signed for all subjects. The clinical characteristics of all the subjects are listed in Table 1.

This study was originally conducted to investigate the synergistic effect of GH and testosterone on the metabolic changes of puberty (14). Ten prepubertal boys with clinical and biochemical evidence of GH deficiency were studied. Seven had isolated GH deficiency and three had organic GH deficiency and were on stable thyroid replacement. Subjects underwent a baseline series of metabolic studies and were then randomized to two groups. The first group was given testosterone enanthate, 50–75 mg (depending on weight) im every 4 wk. Three days after the second testosterone injection, the studies were repeated. The subjects were then started on recombinant human GH, 0.042 mg/kg·d, sc. Three days after the third testosterone injection, the studies were repeated a third time. The boys in the second group were treated identically, except the GH was started with the first testosterone injection and stopped after the second testosterone injection. After the third testosterone injection, GH was started or continued for all the subjects.

Study 2

This study was designed to investigate the gender differences in the metabolic actions of GH (15). Fifteen adolescents (eight boys, seven girls) with short stature due to GH deficiency or idiopathic short stature were studied. Subjects underwent a baseline series of metabolic studies and were started on recombinant human GH, 0.042 mg/kg·d, sc. Studies were repeated after 8 wk. Subjects were then continued on GH and followed up for 1 yr.

Study 3

This study was originally conducted to investigate whether boys with CDGM have a hypermetabolic state as measured by changes in total energy expenditure by doubly labeled water methods (16). Twelve boys with CDGM along with 11 healthy boys with ages comparable with the CDGM group (age-matched controls) and 12 healthy boys with heights comparable with the CDGM group (height-matched controls) were studied. Subjects with either CDGM or healthy control subjects (height matched or age matched) underwent a single series of studies, and cross-sectional comparisons were made.

Anthropometrics

Height was determined using a wall-mounted Harpenden stadiometer. Height and growth velocity SD scores were calculated using GenenCalc software (version 1.3; Genentech, Inc., South San Francisco, CA).

Assays

Plasma from all the above studies was stored at –80 C. Samples were used for RIA for plasma NTproCNP at the Christchurch Cardioendocrine Research Group (Christchurch School of Medicine, University of Otago, Otago, New Zealand) as described (11, 12). The limit of detection of this assay for human NTproCNP is 0.4 pmol/liter. Within- and between-assay coefficients of variation were 6.1 and 9.4%, respectively, at 40 pmol/liter. IGF-I was measured by RIA using commercial kits (Diagnostic Systems Laboratory, Webster, TX). IGF-I SD scores were calculated using reference data provided by the kit manufacturer.

Statistical analysis

For study 1, there was no difference between the two treatment order groups, and the data from both groups were combined. Changes in NTproCNP or IGF-I levels among the three treatments (baseline, testosterone alone, and testosterone with GH) were tested using ANOVA with repeated measures, with Holm’s pair-wise post hoc comparisons. For study 2, changes in NTproCNP or IGF-I levels between the two treatments (baseline and GH) were tested with paired t test. For study 3, NTproCNP levels from the three cohorts (CDGM, height-matched controls, and age-matched controls) were compared using ANOVA with Holm’s pair-wise post hoc comparisons. Correlation between NTproCNP and IGF-I was done by fitting a line by least squares and performing linear regression analysis. The above analyses were done using Primer of Biostatistics software (version 5.0; McGraw Hill Professional, New York, NY). Nonlinear correlation analyses for age and NTproCNP and age and IGF-I were performed by sequentially fitting polynomial curves of increasing order by least squares. The resulting explained variances (r²) were then compared using ANOVA. The cubic curve provided the best fit in both cases and this regression analysis is reported. Data are expressed as mean ± SD. Significance was assumed for P < 0.05.

	Results

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Study 1

In this study, stable isotope methods demonstrated that in prepubertal, GH-deficient boys, testosterone and GH each had anabolic effects on protein metabolism and body composition and that these effects are synergistic when these treatments were combined (14).

Before any treatment, NTproCNP levels in these boys were 31.2 ± 3.7 pmol/liter (mean ± SD, n = 10) (Fig. 1). After 4 wk of testosterone treatment, levels rose to 50.0 ± 5.7 pmol/liter. After 4 wk of combined GH and testosterone treatment, levels were 57.2 ± 14.4 pmol/liter [ANOVA with repeated measures P < 0.001; baseline vs. testosterone, P < 0.001; baseline vs. GH and testosterone P < 0.001; testosterone vs. GH and testosterone, P = not significant (ns)].

View larger version (13K): [in this window] [in a new window]   FIG. 1. NTproCNP levels in GH-deficient boys. Ten prepubertal boys were studied at baseline, after 4 wk of testosterone treatment (Test, upper panel), and after 4 wk of testosterone and GH treatment (Test + GH, lower panel). Points show the data for each individual, bars the mean, and error bars the SD. The differences are significant (ANOVA with repeated measures, P < 0.001). *, P < 0.001.

Growth velocity for these boys at baseline was 5.3 ± 0.9 cm/yr (growth velocity SD score –1.0 ± 2.0) and was 9.8 ± 1.3 cm/yr (SD score +3.5 ± 3.1) during the first year of GH treatment.

Study 2

Data from study 2 also demonstrated the anabolic effects of GH on protein metabolism and body composition in short children. There was a significant protein-anabolic and lipolytic effect of GH, but there was no significant difference between the genders, except for a markedly higher increase in IGF-I in boys (15).

Before GH treatment, NTproCNP levels in these children were 33.0 ± 10.9 pmol/liter (n = 15). After 2 months of GH treatment, levels rose to 42.9 ± 9.9 pmol/liter (P < 0.001) (Fig. 2). There were no differences between the boys and girls (data not shown).

View larger version (11K): [in this window] [in a new window]   FIG. 2. NTproCNP levels in short children. Fifteen children (seven girls, eight boys) with short stature (GH deficiency or idiopathic short stature) were studied at baseline and after 2 months of GH treatment. *, P < 0.001.

Growth velocity for these children before treatment was 4.8 ± 2.1 cm/yr (growth velocity SD score –1.9 ± 2.9) and rose to 9.5 ± 2.3 cm/yr (SD score +3.8 ± 3.3) during the first year of GH treatment. There were no differences in growth velocity between the sexes.

Study 3

Study 3 showed that boys with constitutional delay of growth and maturation had higher rates of energy expenditure than age-matched or height-matched controls (16).

NTproCNP levels in boys with CDGM were 31.0 ± 2.9 pmol/liter (n = 12). Levels from age-matched healthy boys were higher at 39.8 ± 5.9 pmol/liter (n = 11) but were comparable in height-matched healthy boys, 33.8 ± 7.8 pmol/liter (n = 12) (ANOVA, P < 0.005, CDGM vs. age-matched controls, P < 0.001; CDGM vs. height-matched controls, P = ns) (Fig. 3).

View larger version (16K): [in this window] [in a new window]   FIG. 3. NTproCNP levels in boys with constitutional delay of growth and maturation. Boys with CDGM (n = 12) were compared with age-matched controls (n = 11) and height-matched controls (n = 12). The differences are significant (ANOVA, P < 0.005).

View larger version (13K): [in this window] [in a new window]   FIG. 4. NTproCNP and IGF-I levels in healthy boys. Levels from boys participating as healthy controls in study 3 are plotted by age. Cubic curves were fitted by least squares. Upper panel, NTproCNP levels. Lower panel, IGF-I levels (divide by 7.6 for nanomoles per liter).

View larger version (19K): [in this window] [in a new window]   FIG. 5. NTproCNP levels in healthy boys. Levels are grouped by genitalia Tanner stage. Boys at Tanner stages III and IV were combined. For Tanner stage I, n = 9; Tanner stage II, n = 5; Tanner stage III/IV, n = 5; and Tanner stage V, n = 4. The differences are significant (ANOVA, P < 0.02).

To compare NTproCNP levels between GH deficiency and idiopathic short stature, the subjects in studies 1 and 2 were combined and grouped by peak GH level to provocative stimulation. Subjects with probable GH deficiency (peak GH < 5 ng/ml, n = 10, eight boys, two girls, aged 12.9 ± 1.4 yr) were compared with those with probable GH sufficiency (peak GH > 7 ng/ml, n = 8, four boys, four girls, aged 13.2 ± 0.7 yr). Absolute growth velocity (5.0 ± 1.5 vs. 5.1 ± 1.6 cm/yr, P = ns) and growth velocity SD score (–1.8 ± 2.6 vs. –1.3 ± 2.4, P = ns) were not different between the groups. IGF-I levels were significantly lower in the probable GH deficiency group (229 ± 122 vs. 398 ± 132 ng/ml, P < 0.05), as were IGF-I SD scores (–1.4 ± 0.6 vs. –0.6 ± 0.7, P < 0.05). NTproCNP levels were not different between the groups (34.8 ± 5.5 vs. 33.8 ± 11.0 pmol/liter, P = ns). It should be noted that these comparison groups were not perfectly matched. Hence, there is an increased possibility that other factors contribute to the similarities and differences found between the groups.

	Discussion

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For this report, we measured NTproCNP levels in children with short stature and healthy adolescent boys. The subjects with short stature carried one of several diagnoses, GH deficiency, idiopathic short stature, or constitutional delay of growth and maturation. NTproCNP levels were remarkably similar in these subjects and did not differ among the subjects depending on the etiology of the short stature. Data in healthy children are not yet sufficient to define the complete reference range for NTproCNP. However, for boys with CDGM, levels were lower than those for age-matched controls, congruent with their disordered growth.

This report is the first to describe NTproCNP in children receiving growth-promoting therapy. GH treatment in children with GH deficiency or idiopathic short stature was associated with an increase in NTproCNP levels along with increases in growth velocity and in IGF-I levels. In prepubertal boys with GH deficiency, testosterone treatment was also associated with a vigorous increase of NTproCNP as well as IGF-I. The duration of treatment was too short to assess the effect of testosterone alone on growth velocity in these boys.

Cross-sectional data from healthy boys showed a peak in NTproCNP at about 14 yr of age and genitalia Tanner stage III/IV. Growth velocity information was not obtained from these subjects. However, previous reports have shown the peak growth velocity during the puberty in healthy Caucasian boys occurs at 13.6 ± 1.1 yr (18). These data are suggestive of a relationship between NTproCNP and growth velocity during the pubertal growth spurt. Taken together with the stimulatory effect of testosterone, the data are the first to strongly implicate increased CNP synthesis during the pubertal growth spurt, at least in boys. The pattern and timing of the changes in NTproCNP are paralleled by the changes in IGF-I during adolescence.

Much of the data presented here show a correlation with NTproCNP and IGF-I, and it could be argued that CNP production (and hence NTproCNP levels) are simply stimulated by IGF-I, independently of growth. To address this, we compared children with slow growth due to GH deficiency and slow growth due to idiopathic short stature. There was no difference in the growth velocities between these groups. Nor was there a difference in the NTproCNP levels, despite a large difference in IGF-I levels. In addition, boys with short stature had a greater increase in IGF-I levels in response to GH treatment than girls, yet NTproCNP levels increased equally in both sexes, as did growth velocity. Previous findings have shown that, during early childhood when growth velocity is decreasing, plasma concentrations of NTproCNP fall (12), whereas levels of IGF-I increase (17). And finally, previous work in healthy lambs (13) has shown that short-term GH treatment did not increase metacarpal growth velocity despite a doubling in IGF-I level; NTproCNP levels did not change during this treatment. In each of these cases, NTproCNP levels paralleled growth velocity, not IGF-I level. Together, these findings argue against direct CNP stimulation by circulating IGF-I but do not preclude the possibility that local (growth plate) production of IGF-1 affects CNP synthesis.

There are several limitations to this study. First, these are retrospective studies using plasma stored frozen for periods up to 5 yr. Although NTproCNP is relatively stable (8% loss of immunoreactivity in stored plasma per year), levels reported here are likely to be lower than those detailed in previous studies (12). Such losses should be proportionate and should not affect the responses reported here. Second, the number of subjects studied was small, and measurements of growth velocity, when made, were not closely aligned temporally with plasma NTproCNP measurements. A relationship between NTproCNP level and growth velocity has been previously reported during normal growth (12), and we have shown here that growth-promoting therapy increased both. Clearly prospective and more focused studies are now required to better define these relationships during the early phases of growth stimulation.

It is our assertion that GH and IGF-I are primary drivers of growth, whereas CNP is a mediator of the process of growth. When the signals for rapid growth are in place, the growth plates are maximally active. As part of this activation, CNP production within the growth plate is increased, which in turn drives matrix synthesis and chondrocyte differentiation (1). Because NTproCNP is a byproduct of CNP production, NTproCNP is therefore a likely biomarker of the process of growth, reflecting the activity of the growth plate and hence linear growth.

In summary, NTproCNP is produced in the growth plate and levels correlate with growth velocity (12). Children with short stature due to GH deficiency, idiopathic short stature, or CDGM have comparable baseline levels of NTproCNP, and NTproCNP shows a marked increase in response to GH or testosterone treatment. And finally, plasma NTproCNP levels are increased during spontaneous puberty in boys. These studies confirm that CNP production is related to growth during times of slow and rapid growth.

NTproCNP may have clinical utility in the evaluation of children with short stature and in monitoring growth promoting therapy. NTproCNP levels increased long before changes in growth velocity could be determined. Hence, levels of this peptide may prove to be an early marker of efficacy. More studies are required to explore this potential, starting with an effort to better define the reference range in healthy children.

	Acknowledgments

 
We are grateful to Susan Welch, Kim Walker, and Annie Rini for the coordination and conduct of these studies; the nursing staff of the Wolfson Children’s Hospital Clinical Research Center for the expert care of our patients; Shawn Sweeten and Brenda Sager for technical laboratory assistance; and Suzanne Murphy for assistance with the statistical analysis.

	Footnotes

 
This work was supported by National Institutes of Health Grants RO1DK43802, Genentech Foundation for Endocrinology Research, and Nemours Research Programs. J.C.H. is a commissioned officer of the U.S. Public Health Service, Department of Health and Human Services. NTproCNP-related costs were funded in part by the Canterbury Medical Research Foundation (New Zealand) and the New Zealand Lottery Grants Board.

Disclosure Statement: N.M. and R.C.O. have research grants from and serve on advisory panels for pharmaceutical companies that sell GH. T.C.R.P., T.G.Y., and E.A.E. have the patent pending for NTproCNP peptides and uses thereof. J.C.H. has nothing to disclose.

First Published Online August 7, 2007

Abbreviations: CDGM, Constitutional delay of growth and maturation; CNP, C-type natriuretic peptide; ns, not significant; NTproCNP, amino-terminal propeptide of CNP.

Received March 13, 2007.

Accepted August 1, 2007.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Olney, R. C. Articles by Mauras, N. Search for Related Content PubMed PubMed Citation Articles by Olney, R. C. Articles by Mauras, N. Related Collections Neuroendocrinology and Pituitary Pediatric Endocrinology Female Endocrinology Male Endocrinology