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Longitudinal Circulating Procollagen-markers PRO-C1 and PRO-C2 Reflect Pubertal Growth Spurt in Healthy Adolescents
Li Juel Mortensen1,2, Yi He3, Martin Blomberg Jensen4,5
1Department of Growth and Reproduction, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.
Insights
New biomarkers, procollagen type I (PRO-C1) and type II (PRO-C2), show promise for monitoring growth in children. These markers reflect both natural growth spurts and growth hormone (GH) treatment efficacy.
Area of Science:
- Pediatric endocrinology
- Biomarker discovery
- Skeletal development
Background:
- Growth hormone (GH) and IGF-I stimulate epiphyseal growth plate development.
- Serum IGF-I is a standard marker for GH treatment efficacy and safety in children.
- IGF-I provides limited guidance for non-GHD children, necessitating novel biomarkers for linear growth.
Purpose of the Study:
- To evaluate the association between linear growth during pubertal transition and circulating levels of procollagen type I (PRO-C1) and type II (PRO-C2).
- To establish reference intervals for PRO-C1 and PRO-C2 in healthy children and adolescents.
- To assess PRO-C1 and PRO-C2 as potential biomarkers for endogenous and GH-induced linear growth.
Main Methods:
- Analysis of 1700 serum samples from 213 healthy children and adolescents (aged 5-16 years) from the Copenhagen Puberty study.
- Assessment of peak height velocity (PHV), pubertal development, IGF-I, sex-steroids, PRO-C1, and PRO-C2.
- Determination of PRO-C1 and PRO-C2 in short children born small-for-gestational-age (SGA) before and after GH treatment.
Main Results:
- Established age-, sex-, and puberty-related reference intervals for PRO-C1 and PRO-C2.
- PRO-C1 and PRO-C2 levels significantly increased with age and pubertal development.
- PRO-C1 and PRO-C2 peaked at the time of PHV, preceding IGF-I and sex-steroids, and were associated with increased height SDS and velocity.
- GH treatment significantly increased PRO-C1 and PRO-C2 levels in prepubertal children.
Conclusions:
- PRO-C1 and PRO-C2 levels longitudinally track normal and disordered growth patterns.
- PRO-C1 and PRO-C2 are proposed as potential biomarkers for monitoring endogenous and GH-induced linear growth.
- These novel biomarkers may offer improved guidance for clinicians in assessing pediatric growth.
Introduction:
Epiphyseal growth plate development is stimulated by GH and IGF-I. Serum IGF-I is applied as an efficacy and safety marker, monitoring growth in short GH-treated children. However, IGF-I offers poor guidance to clinicians, especially in children without GHD. Thus, novel biomarkers reflecting endogenous and GH-induced linear growth are needed. We evaluated the association between linear growth during pubertal transition and circulating levels of procollagen type I and II (PRO-C1, PRO-C2).
Methods:
We included 1700 serum samples from 213 healthy children and adolescents (51% female), aged 5-16 years, from the prospective longitudinal Copenhagen Puberty study, followed between 2006--2014. We assessed peak height velocity (PHV), pubertal development, serum IGF-I, sex-steroids (LC-MS/MS), and PRO-C1, PRO-C2 (immunoassays). Additionally, PRO-C1 and PRO-C2 were determined in short children born small-for-gestational-age (SGA) before and after 12 months of GH-treatment.
Results:
Age-, sex-, and puberty-related reference intervals for PRO-C1 and PRO-C2 concentrations were established. PRO-C1 and PRO-C2 increased significantly with age and pubertal development (Tanner B1 through B3, p<0.0001; G1 through G4, p<0.001). During growth spurt, PRO-C1 and PRO-C2 were associated with increased height standard deviation score (SDS) and height velocity, both reached peak concentrations at the time of PHV, earlier than IGF-I and sex-steroids, followed by a rapid decline. In GH-treated prepubertal children, PRO-C1 increased from 0.70 to 3.78 SDS (p<0.0001) and PRO-C2 from -2.07 to 0.69 SDS (p=0.0055).
In Conclusion:
we present longitudinal changes in PRO-C1 and PRO-C2 in normal and disordered growth, suggesting PRO-C1 and PROC-2 as potential biomarkers of endogenous and GH-induced linear growth.
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