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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 10 5156-5160
Copyright © 2004 by The Endocrine Society

Cartilage Oligomeric Matrix Protein Increases in Serum after the Start of Growth Hormone Treatment in Prepubertal Children

R. Bjarnason, B. Andersson, H. S. Kim, B. Olsson, D. Swolin-Eide, R. Wickelgren, B. Kriström, B. Carlsson, K. Albertsson-Wikland and L. M. S. Carlsson on behalf of the Swedish Study Group for Growth Hormone Treatment

Göteborg Pediatric Growth Research Center (R.B., B.A., H.S.K., D.S.-E., R.W., B.K., K.A.-W.), Department of Pediatrics, The Institute of the Health of Women and Children, 416 85 Göteborg, Sweden; RCEM (B.A., B.O., B.C., L.M.S.C.), Department of Internal Medicine, The Sahlgrenska Academy at Göteborg University, 413 45 Göteborg, Sweden; Department of Pediatrics (R.B.), Landspitali University Hospital, 101 Reykjavik, Iceland; and Department of Pediatrics (H.S.K.), Daini Hospital, Tokyo Women’s Medical University, 116-8567 Tokyo, Japan

Address all correspondence and requests for reprints to: Ragnar Bjarnason, The Sahlgrenska Academy at Göteborg University, Department of Pediatrics, Göteborg Pediatric Growth Research Center, The Queen Silvia Children’s Hospital, S-416 85 Göteborg, Sweden. E-mail: ragnar.bjarnason{at}vgregion.se.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Both GH and IGF-I stimulate bone growth, but the molecular mechanisms mediating their effects on the growth plate are not fully understood. We measured gene expression by microarray analysis in primary cultured human chondrocytes treated with either GH or IGF-I. One of the genes found to be up-regulated by both GH and IGF-I was that encoding cartilage oligomeric matrix protein (COMP). This protein is predominantly found in the extracellular matrix of cartilage. Mutations in the COMP gene have been associated with syndromes of short stature. To verify that COMP is regulated by GH in vivo, we measured COMP levels in serum in short children treated with GH. The study included 113 short prepubertal children (14 girls and 99 boys) with a mean (± SD) age of 8.84 ± 2.76 yr, height SD score of –2.74 ± 0.67, and IGF-I SD score of –1.21 ± 1.07 at the start of GH administration. Serum levels of COMP were 1.58 ± 0.28, 1.83 ± 0.28 (P < 0.0001), 1.91 ± 0.28 (P < 0.0001), 1.78 ± 0.28 (P < 0.001), and 1.70 ± 0.24 (P < 0.05) µg/ml at baseline and after 1 wk and 1, 3, and 12 months, respectively.

In conclusion, we have demonstrated that COMP expression is up-regulated by both GH and IGF-I in primary cultured human chondrocytes. Furthermore, serum levels of COMP increase after the start of GH treatment in short children.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
LONGITUDINAL GROWTH RESULTS from chondrocyte proliferation and differentiation in the growth plate. GH is considered to be an important regulator of linear growth in childhood. Both GH and IGF-I have direct actions on the epiphyseal growth plate in which GH exerts its main effects on the germinal zone and IGF-I on the proliferative zone (1, 2). GH also increases local IGF-I expression in the epiphyseal growth plate, i.e. GH has both direct and indirect effects on the growth plate. The skeleton develops by endochondral ossification, a process characterized by differentiation of mesenchymal cells into chondrocytes, which form cartilage anlagen of the future bone. The chondrocytes proliferate, mature, and become hypertrophic and eventually calcify. This calcified cartilage is then invaded by osteoclasts, osteoblasts, and blood vessels that resorb the cartilage and replace it with bone matrix (1, 2, 3).

Although there is considerable knowledge of how GH stimulates linear growth, there are numerous areas in this process that are not fully understood. Much effort has been put into the diagnosis of GH deficiency (4, 5). However, it is well established that the growth response to GH treatment varies widely in children (6) and that the growth response can serve as an indicator of GH responsiveness. Validated models for predicting the growth responses of children to GH treatment have been developed (7, 8). Although it is clear that the tissue sensitivity to GH differs among children, standardized doses are still given in clinical practice in the majority of cases. This is due to the lack of understanding of the mechanisms governing the growth response and to the absence of good markers of individual responsiveness to GH. Tissue sensitivity to GH is likely to be regulated by a number of genes, many of which have not been considered a part of the GH/IGF-I axis.

The aim of this study was to increase our understanding of the mechanisms involved in growth regulation by identification of novel genes that are regulated in response to both GH and IGF-I.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Cell culture

Cultured human primary chondrocytes were established from an extirpated extra thumb from a 1-yr-old boy. Cells were cultured in DMEM/F12 (1:1, vol/vol) (Life Technologies, Inc., Paisley, UK) containing 10% (vol/vol) fetal calf serum (FCS; Bio Whittaker, Verviers, Belgium), Fungizone (500 µg/l; Life Technologies, Inc.), gentamicin sulfate (50 mg/l; Biochrom KG, Berlin, Germany), L-glutamine (2 mmol/liter; Life Technologies), and L-ascorbic acid (100 mg/l; Merck, Darmstadt, Germany) in a humidified 5% CO2 atmosphere at 37 C. Cells were routinely tested and found to be negative for mycoplasma infections. Cells in passage 3 were used for the experiment. Cells were grown to confluence and then rinsed twice with DMEM without phenol red (Life Technologies) before they were starved for 27 h in DMEM without phenol red and without any serum. They were then stimulated by GH [50 ng/ml, Genotropin, batch 28157B51; 36IE/KY (12 mg), supplied by Pfizer AB, Täby, Sweden] or IGF-I (50 ng/ml, lot 99H0295, Sigma, St. Louis, MO) for 12 h before being harvested for RNA preparation.

Preparation of cRNA and microarray hybridization

RNA from the primary cultured human chondrocytes was isolated using an RNeasy kit (Qiagen, Valencia, CA) and transcribed into cDNA using the Superscript Choice system (Life Technologies). Biotin-labeled target cRNA was synthesized from the cDNA by in vitro transcription using a BioArray high-yield RNA transcript labeling kit (Enzo Diagnostics Inc., Farmingdale, NY). Hybridization, washing, staining, and detection were performed according to the manufacturer’s instructions using a fluidics station and confocal scanner (Affymetrix, Santa Clara, CA). The HU95A arrays used are composed of 12,000 probe sets for known human genes. To allow for comparisons between microarrays, the average intensity was scaled to 500.

Analysis of microarray data

After visual inspection for hybridization artifacts of the scanned output files Microarray software (Suite 5.0, Affymetrix) was used for the analysis of differences in gene expression between GH- or IGF-I-stimulated chondrocytes, compared with controls. Each treatment and control group was run in duplicate. The two GH and two IGF-I microarrays were compared separately with the two control microarrays, creating four comparison files for GH vs. controls and four comparison files for IGF-I vs. controls. Genes with different expression levels in chondrocytes cultured with GH or IGF-I vs. controls were identified by the difference call (Diff Call) algorithm (Affymetrix), an algorithm based on signal intensity and quality. With the Diff Call, a gene is classified as increased, marginally increased, no change, marginally decreased, or decreased. Genes having a Diff Call of increased, marginally increased, marginally decreased, or decreased in three of the four comparisons were selected for further investigation. We further selected the genes that were regulated similarly, i.e. up-regulated or down-regulated, by both GH and IGF-I treatment. The average fold change was calculated from the four comparisons. Down-regulated transcripts are given a negative fold change.

Study group

A group of 113 short, prepubertal, Swedish children (14 girls and 99 boys) with a broad range of maximal GH response (GHmax) during an arginine-insulin tolerance test (AITT) (1–34.7 µg/liter) was treated with daily injections of GH (0.033 mg/kg) and followed up for at least 1 yr. The clinical characteristics of the patients are given in Table 1Go. Of the 113 children, 82 were diagnosed as having isolated idiopathic GH insufficiency, defined as a GHmax less than 10 µg/liter during an AITT using the World Health Organization (WHO) international reference preparation (IRP) 80/505, and 31 were short but did not have GH insufficiency, defined as a GHmax above 10 µg/liter during an AITT using the WHO IRP 80/505 (9, 10). All children were included in the Swedish national registry for GH treatment or clinical trials for short children. The children were well nourished, free from chronic disease, and had no dysmorphic features. For all children in the study, gestational age at birth was more than 30 wk, and their birth weight and birth length were above –2.5 SD scores (SDS) for gestational age.


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  		TABLE 1. Characteristics of the study group of prepubertal children (n = 113; 14 girls, 99 boys)

 
The study was approved by the Ethical Committees of the Medical Faculties of the Universities of Göteborg, Lund, Uppsala, Linköping, and Umeå and the Karolinska Institute (Stockholm, Sweden). Informed consent was obtained from the parents of each child and from the child if old enough.

Study protocol

Pretreatment investigations. Endocrine investigations were performed during the pretreatment year. The children underwent an AITT, and the GHmax was estimated (6, 11, 12). A blood sample was obtained for determination of cartilage oligomeric matrix protein (COMP), IGF-I, and IGF-binding protein (IGFBP)-3 concentrations.

Treatment follow-up. Blood samples were taken at the start of GH treatment and at least at two of the following points in time:1 wk, 1 month, 3 months, and 1 yr after the start of GH treatment. The samples were generally taken between 1400 and 1800 h, i.e. approximately 24 h after the last GH injection.

Auxology

Growth of the children was recorded at health care units from birth to the time of inclusion in the study, i.e. 1 yr before the start of GH treatment. Thereafter, height was measured at pediatric endocrine units at university clinics. Height and weight parameters were transformed into SDS for sex and age using the childhood component of the infancy, childhood, and puberty components growth model of Karlberg (9). The auxological variables included in the statistical analysis are listed in Table 1Go.

Protein analysis

COMP. Concentrations of serum COMP were measured in duplicate by an ELISA (Kamiya Biomedical Co., Seattle, WA). The assay has a detection range of 10–80 ng/ml. All samples were analyzed using the same assay batch, and samples from each patient were run in the same assay. Only COMP values with an interassay coefficient of variation less than 15% were included. In our hands, the assay had an interassay coefficient of variation of 10.0% at 1.0 µg/ml and 8.7% at 1.3 µg/ml.

GH. In most samples, serum GH concentrations were measured by a polyclonal antibody-based immunoradiometric assay (Pharmacia Diagnostics) using standard WHO IRP 80/505. When other methods or standards were used, the GH concentrations were transformed into comparable levels (11, 13).

IGF-I. Concentrations of serum IGF-I were measured by an IGFBP-blocked RIA without extraction and in the presence of an approximately 250-fold excess of IGF-II (Mediagnost GmbH, Tubingen, Germany) (6, 14).

IGFBP-3. Serum IGFBP-3 concentrations were measured by a polyclonal antibody-based RIA (Mediagnost GmbH), as reported previously (6, 14). Serum concentrations of IGF-I and IGFBP-3 were converted into SDS, using a prepubertal reference obtained in our laboratory from healthy young children of normal (± 2 SD) stature (7, 14).

Statistical methods

Statistical analyses were performed using SPSS (version 11.5, SPSS, Inc., Chicago, IL) and Origin (version 5.0, Microcal Software, Inc., Northampton, MA). Data are presented as means ± SD. Pearson’s correlation coefficient was used to calculate correlations at the individual level. Independent t tests were used to test significance at the group level.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Identification of GH- and IGF-I-responsive genes in human chondrocytes

Based on ranking of GH and IGF-I responsiveness in the microarray analyses, 11 candidate genes were regulated in response to both GH and IGF-I (Table 2Go), and all were increased, compared with controls. By combining the microarray ranking with a literature search, the COMP gene was identified as a possible candidate gene because of its association with known conditions of short stature (15, 16). This gene was selected for further studies.


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  		TABLE 2. Genes regulated by both GH and IGF-I in cultured human chondrocytes

 
Serum COMP concentrations at the start of GH treatment

Serum COMP concentrations at baseline correlated with baseline serum IGF-I SDS (r = 0.19; P = 0.045) and serum IGFBP-3 SDS (r = 0.19; P = 0.042). In contrast, there was no significant correlation between COMP concentrations at the onset of treatment and height SDS (r = 0.01; P = 0.95), age (r = –0.07; P = 0.49), sex (P = 0.41), or GHmax during an AITT (r = 0.11; P = 0.24).

Serum COMP concentrations during GH treatment

Mean serum COMP group levels increased significantly after the start of GH treatment, from 1.58 ± 0.28 to 1.83 ± 0.28, 1.91 ± 0.28, 1.78 ± 0.28, and 1.70 ± 0.24 µg/ml after 1 wk, 1 month, 3 months, and 12 months, respectively (Fig. 1Go). There was a significant correlation between the individual change in COMP levels and IGF-I SDS (r = 0.28; P = 0.035) as well as for the change in IGF-I SDS after 3 months of treatment with GH (r = 0.35; P = 0.00661) (Fig. 2Go). Similarly, there was a correlation between the change in COMP and IGFBP-3 SDS at 3 months (r = 0.30; P = 0.022).



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  		FIG. 1. Mean levels of serum COMP at the start of GH treatment and after 1 wk, 1 month, 3 months, and 1 yr of treatment. Values are means ± SEM. *, P < 0.05, ***, P < 0.0001, compared with baseline.

 


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  		FIG. 2. Individual change in serum COMP values after 3 months of GH treatment plotted against individual changes in IGF-I SDS after 3 months of GH treatment.

 
There was no correlation between changes in COMP concentrations after 3 months and the pretreatment values of GHmax during an AITT (r = –0.04; P = 0.79), height SDS (r = 0.03; P = 0.82), weight SDS (r = 0.04; P = 0.77), or body mass index (r = 0.06; P = 0.66).

Changes in COMP in relation to the growth response to GH

There was no correlation between the first-year growth response, expressed as change in height SDS, from the start of GH treatment, and the COMP levels at any time point (r = –0.02; P = 0.82; r = –0.01; P = 0.96; r = 0.22; P = 0.089; r = 0.96; P = 0.46; r = 0.12; P = 0.28) at baseline and after 1 wk, 1 month, 3 months, and 12 months, respectively.


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
COMP was identified as a GH- and IGF-I-responsive gene in human chondrocytes by stimulating primary cultures of human chondrocytes with GH and IGF-I and analyzing changes in gene expression using a microarray technique. Furthermore, it was demonstrated that GH treatment of prepubertal children increases serum COMP levels. This novel parameter of the GH response may be intricately coupled to the GH responsiveness of the cartilage of the growth plate.

COMP is a secreted 550-kDa homopentameric glycoprotein that belongs to the thrombospondin family and is primarily found in the extracellular matrix of cartilage, ligament, and tendon (17, 18, 19, 20, 21). COMP contains an N-terminal pentamer formation domain, four epidermal growth factor-like domains, eight calmodulin-like repeats (CLRs), and a C-terminal globular domain. The C-terminal globular domain and the CLRs are highly conserved among members of the thrombospondin family (22, 23, 24). More than 60 disease-causing mutations in the COMP gene are known, mostly located within the CLRs or the C-terminal globular domain (23). Mutations in the COMP gene are associated with both pseudoachondroplasia (PSACH) and multiple epiphyseal dysplasia (MED), both of which are inherited in an autosomal dominant fashion and are phenotypically heterogeneous diseases. PSACH is characterized by disproportionate short stature, early-onset osteoarthrosis, and dysplasia of the spine. MED is associated with less severe dysplasia than PSACH and is characterized by average to mild short stature, joint pain, joint laxity, and early-onset osteoarthrosis (25). The COMP protein is predominantly synthesized by chondrocytes, and the highest level of COMP mRNA is detected in chondrocytes in the central region of the growth plate, primarily in the zone of proliferative chondrocytes, but also in the hypertrophic regions (25, 26). The role of COMP in proliferation and differentiation of the epiphyseal growth plate is currently unknown (23). The protein is detectable in synovial fluid and serum by ELISA and has been shown to be elevated in rheumatoid arthritis and osteoarthritis (25). Furthermore, Vilim et al. (27) have shown that no diurnal variations in COMP expression occurred in 16 of 20 patients; in the remaining four, significantly higher levels of COMP were detected in the afternoon. The increase might be due to food intake, physical activity, or some other unknown factor.

COMP is known to interact with collagens types I, II, and IX in a divalent cation-dependent manner. COMP and its proteolytic fragments are released into synovial fluid and serum on joint degradation, suggesting a possible role of COMP in the assembly and maintenance of the extracellular matrix (25). This may also indicate that COMP plays an important role in the growth plate.

The mechanisms by which GH and IGF-I influence COMP expression and serum levels are unknown. GH treatment induced an increase in serum COMP levels, and the changes in COMP levels were positively correlated with the changes in serum concentrations of IGF-I and IGFBP-3 after 3 months of treatment. This response to GH treatment has not, to our knowledge, been previously reported. The induction of both gene expression in cultured chondrocytes and the increase in serum levels of COMP during GH treatment indicate that COMP might be of importance for the growth response to GH treatment. We have not been able to correlate changes in COMP levels after the start of GH treatment with the growth response. However, COMP may still be of importance for growth because GH treatment in children with PSACH appears to have a negative effect on growth rate (28), possibly through increased apoptosis of growth plate chondrocytes (29).

Many factors may influence the correlation between serum levels of COMP and the response to GH. For example, in conditions such as rheumatoid arthritis, reactive arthritis, juvenile chronic arthritis, and osteoarthritis, the increased COMP levels most likely result from the destruction of cartilage. In addition, COMP levels are elevated in marathon runners, suggesting that physical activity influences serum COMP levels in healthy subjects, possibly via the increase in GH secretion that occurs during/after exercise (30, 31, 32).

In conclusion, GH treatment increases serum COMP levels in prepubertal short children, and COMP is a novel GH-responsive gene. The possible role of COMP in growth and the growth response to GH treatment needs to be further elucidated.


   Acknowledgments
 
The Swedish Study Group for Growth Hormone Treatment consists of Kerstin Albertsson-Wikland, Jan Alm, Stefan Aronsson, Jan Gustafsson, Lars Hagenäs, Anders Häger, Sten Ivarsson, Berit Kriström, Claude Marcus, Christian Moell, Karl-Olof Nilsson, Martin Ritzen, Torsten Tuvemo, Ulf Westgren, Otto Westphal, and Jan Åman. We thank Margareta Järnås for invaluable technical support, Anders Lindahl for fruitful discussions, and Sten Rosberg for statistical advice. We are also grateful to all the children and parents who made this study possible.


   Footnotes
 
This work was supported by grants from the Swedish Medical Research Council (7509, 11285, 11331, 11502, 11576), Pfizer, Novo Nordisk, The Swedish Society of Medicine, IngaBritt and Arne Lundberg Forskningsstiftelse, Tore Nilssons Foundation for Medical Research, Åke Wiberg Foundation, and the Magnus Bergvall Foundation.

Abbreviations: AITT, Arginine-insulin tolerance test; CLR, calmodulin-like repeat; COMP, cartilage oligomeric matrix protein; GHmax, maximal GH response; IGFBP, IGF-binding protein; IRP, international reference preparation; PSACH, pseudoachondroplasia; SDS, SD scores; WHO, World Health Organization.

Received March 31, 2004.

Accepted July 28, 2004.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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