Longitudinal Circulating Procollagen-markers PRO-C1 and PRO-C2 Reflect Pubertal Growth Spurt in Healthy Adolescents

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.