Introduction and objective:
The expression of the C-type natriuretic peptide (CNP) gene has been detected in the growth cartilage of the long bones and vertebrae. This article provides an overview of the role of CNP in bone growth and presents the results of the authors’ research on the concentration of the NTproCNP and its relationship with growth velocity and bone markers in healthy school-age children.

Material and methods:
The study involved 75 girls and 59 boys aged from 9.0–11.8 years (mean 10.29±0.74). Body weight, height and lower limb length were measured, and blood samples were collected twice at six-month intervals. In the first serum sample, the concentrations of NTproCNP, C-terminal propeptide type I (CICP), C-terminal telopeptide type I collagen (ICTP) osteocalcin (OC) and bone-specific alkaline phosphatase (BAP) were determined. In the second sample, NTproCNP concentration was assessed.

During the six-month follow-up period, the increase in body height and weight of girls was greater than boys (p<0.000; p=0.003, respectively). While during the first examination the concentration of NTproCNP in girls and boys was similar, during the second examination it was higher in girls than in boys (p=0.04). Weak positive correlations between the increase in body height and NTproCNP, CICP, BAP as well as OC were found. There were no correlations between NTproCNP and the bone markers.

The results suggest that NTproCNP concentration depends on growth velocity in children. There is increasing evidence that a better knowledge of CNP biology contributes to a better understanding of bone growth mechanisms.

AMDM – acromesomelic dysplasia Maroteaux type; BAP – bone-specific alkaline phosphatase; B-boys; BMI – body mass index; BMPs – bone morphogenetic proteins; CICP – C-terminal pro-collagen-type I propeptide; CNP – C-type natriuretic peptide; FGFR3 – fibroblast growth factor receptor 3; FGFs – fibroblast growth factors; G-girls; GC-B – guanylate cyclase B; ICTP – C-terminal telopeptide type I collagen; IGFs – insulin-like growth factors; IHH – indian hedgehog homolog; NPPC – natriuretic peptide precursor C; NPR-A – natriuretic peptide receptor-A; NPR-B – natriuretic peptide receptor-B; NPR-C – natriuretic peptide receptor-C; NTproCNP – amino-terminal propeptide of the C-type natriuretic peptide; OC – osteocalcin; preproCNP – C-type natriuretic peptide prepropeptide; pro-CNP – C-type natriuretic peptide propeptide; PTHrP – parathyroid hormone-related peptide; VEGF – vascular endothelial growth factor.
The authors would like to thank Dr. Maria Kozłowska, an anthropologist, for carrying out all anthropologic measurements and assistance with their interpretation. The authors also thank the children and their families for their involvement and cooperation in this study.
Gawlik A, Mazur A. Peptydy natriuretyczne u dzieci: fizjologia i zastosowanie kliniczne. Pediatr Dypl. 2013; 17(5): 40–45.
Lui JC, Nilsson O, Baron J. Recent research on the growth plate: Recent insights into the regulation of the growth plate. J Mol Endocrinol. 2014 Aug; 53(1): T1–9.
Olney RC, Prickett TC, Yandle TG, et al. Amino-terminal propeptide of C-type natriuretic peptide and linear growth in children: effects of puberty, testosterone, and growth hormone. J Clin Endocrinol Metab. 2007 Nov; 92(11): 4294–8.
Wit JM, Oostdijk W, Losekoot M, et al. Mechanisms in endocrinology: Novel genetic causes of short stature. Eur J Endocrinol. 2016 Apr; 174(4): R145–73.
Prickett TC, A Espiner E. Circulating products of C-type natriuretic peptide and links with organ function in health and disease. Peptides. 2020 Oct; 132: 170363.
Chen WX, Liu HH, Li RX, et al. C-type natriuretic peptide stimulates osteoblastic proliferation and collagen-X expression but suppresses fibroblast growth factor-23 expression in vitro. Pediatr Rheumatol Online J. 2020 Jun 9; 18(1): 46.
Espiner E, Prickett T, Olney R. Plasma C-Type Natriuretic Peptide: Emerging Applications in Disorders of Skeletal Growth. Horm Res Paediatr. 2018; 90(6): 345–357.
Prickett TC, Lynn AM, Barrell GK, et al. Amino-terminal proCNP: a putative marker of cartilage activity in postnatal growth. Pediatr Res. 2005 Aug; 58(2): 334–40.
Suga S, Nakao K, Hosoda K, et al. Receptor selectivity of natriuretic peptide family, atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide. Endocrinology. 1992 Jan; 130(1): 229–39.
Sangaralingham SJ, Burnett JC Jr. Relaxing With C-Type Natriuretic Peptide, the Guanylyl Cyclase B Receptor, and Pericytes. Circulation. 2018 Jul 31; 138(5): 509–512.
Tassano E, Buttgereit J, Bader M, et al. Genotype-Phenotype Correlation of 2q37 Deletions Including NPPC Gene Associated with Skeletal Malformations. PLoS One. 2013 Jun 21; 8(6): e66048.
Hirota K, Furuya M, Morozumi N, et al. Exogenous C-type natriuretic peptide restores normal growth and prevents early growth plate closure in its deficient rats. PLoS One. 2018 Sep 20; 13(9): e0204172.
Nakao K, Osawa K, Yasoda A, et al. The Local CNP/GC-B system in growth plate is responsible for physiological endochondral bone growth. Sci Rep. 2015; 5: 10554.
Jaubert J, Jaubert F, Martin N, et al. Three new allelic mouse mutations that cause skeletal overgrowth involve the natriuretic peptide receptor C gene (Npr3). Proc Natl Acad Sci. U S A. 1999 Aug 31; 96(18): 10278–83.
Yasoda A, Komatsu Y, Chusho H, et al. Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPK-dependent pathway. Nat Med. 2004 Jan; 10(1): 80–6.
Wagner BM, Robinson JW, Lin YW, et al. Prevention of guanylyl cyclase-B dephosphorylation rescues achondroplastic dwarfism. JCI Insight. 2021 Mar 30: 147832.
Fujii T, Hirota K, Yasoda A, et al. Rats deficient C-type natriuretic peptide suffer from impaired skeletal growth without early death. PLoS One. 2018 Mar 22; 13(3): e0194812.
Amano N, Kitoh H, Narumi S, et al. A novel NPR2 mutation (p. Arg388Gln) in a patient with acromesomelic dysplasia, type Maroteaux. Clin Pediatr Endocrinol. 2020; 29(3): 99–103.
Khan S, Basit S, Khan MA, et al. Genetics of human isolated acromesomelic dysplasia. Eur J Med Genet. 2016 Apr; 59(4): 198–203.
Wang W, Song MH, Miura K, et al. Acromesomelic dysplasia, type maroteaux caused by novel loss-of-function mutations of the NPR2 gene: Three case reports. Am J Med Genet A. 2016 Feb; 170A(2): 426–434.
Olney RC, Bükülmez H, Bartels CF, et al. Heterozygous mutations in natriuretic peptide receptor-B (NPR2) are associated with short stature. J Clin Endocrinol Metab. 2006 Apr; 91(4): 1229–32.
Vasques GA, Amano N, Docko AJ, et al. Heterozygous mutations in natriuretic peptide receptor-B (NPR2) gene as a cause of short stature in patients initially classified as idiopathic short stature. J Clin Endocrinol Metab. 2013 Oct; 98(10): E1636–44.
Bocciardi R, Ravazzolo R. C-type natriuretic peptide and overgrowth. Endocr Dev. 2009; 14: 61–6.
Miura K, Kim OH, Lee HR, et al. Overgrowth syndrome associated with a gain-of-function mutation of the natriuretic peptide receptor 2 (NPR2) gene. Am J Med Genet A. 2014 Jan; 164A(1): 156–63.
Olney RC, Permuy JW, Prickett TC, et al. Amino-terminal propeptide of C-type natriuretic peptide (NTproCNP) predicts height velocity in healthy children. Clin Endocrinol (Oxf). 2012 Sep; 77(3): 416–22.
Diemar SS, Lylloff L, Ronne MS, et al. Reference intervals in Danish children and adolescents for bone turnover markers carboxy-terminal cross-linked telopeptide of type I collagen (ß-CTX), pro-collagen type I N-terminal propeptide (PINP), osteocalcin (OC) and bone-specific alkaline phosphatase (bone ALP). Bone. 2021 May; 146: 115879.
Bayer M. Reference values of osteocalcin and procollagen type I N-propeptide plasma levels in a healthy Central European population aged 0–18 years. Osteoporos Int. 2014 Feb; 25(2): 729–36.
Shao J, Zhou SS, Qu Y, et al. Correlation between bone turnover and metabolic markers with age and gender: a cross-sectional study of hospital information system data. BMC Musculoskelet Disord. 2020 Sep 10; 21(1): 603.
Gajewska J, Klemarczyk W, Ambroszkiewicz J, et al. Associations between IGF-I, IGF-binding proteins and bone turnover markers in prepubertal obese children. J Pediatr Endocrinol Metab. 2015 May; 28(5–6): 563–9.
Rauchenzauner M, Schmid A, Heinz-Erian P, et al. Sex- and age-specific reference curves for serum markers of bone turnover in healthy children from 2 months to 18 years. J Clin Endocrinol Metab. 2007 Feb; 92(2): 443–9.
Ladang A, Rousselle O, Huyghebaert L, et al. Parathormone, bone alkaline phosphatase and 25-hydroxyvitamin D status in a large cohort of 1200 children and teenagers. Acta Clin Belg. 2020 May 22: 1–6.
Vincent A, Souberbielle JC, Brauner R. Comparison of two bone markers with growth evolution in 74 girls with central precocious puberty. BMC Pediatr. 2018 Jul 9; 18(1): 224.
Chlebna-Sokół D, Konstantynowicz J, Abramowicz P, et al. Evidence of a significant vitamin D deficiency among 9–13-year-old Polish children: results of a multicentre study. Eur J Nutr. 2019 Aug; 58(5): 2029–2036.4
Olney RC, Salehi P, Prickett TC, et al. Dynamic response of C-type natriuretic peptide and its aminoterminal propeptide (NTproCNP) to growth hormone treatment in children with short stature. Clin Endocrinol (Oxf). 2016 Oct; 85(4): 561–8.
Kondo E, Yasoda A, Fujii T, et al. Increased Bone Turnover and Possible Accelerated Fracture Healing in a Murine Model With an Increased Circulating C-Type Natriuretic Peptide. Endocrinology. 2015 Jul; 156(7): 2518–29.
Bükülmez H, Khan F, Bartels CF, et al. Protective effects of C-type natriuretic peptide on linear growth and articular cartilage integrityin a mouse model of inflammatory arthritis. Arthritis Rheumatol. 2014 Jan; 66(1): 78–89.
Prickett TC, Hector-Taylor J, Olney RC, et al. Acute inflammation in young children inhibits C-type natriuretic peptide. Pediatr Res. 2013 Aug; 74(2): 191–5.
Topçu S, Özhan B, Alkan A, et al. Plasma Amino-Terminal Propeptide of C-Type Natriuretic Peptide Concentration in Normal-Weight and Obese Children. J Clin Res Pediatr Endocrinol. 2017 Dec 15; 9(4): 308–314.
Olney RC, Prickett TC, Espiner EA, et al. C-type natriuretic peptide plasma levels are elevated in subjects with achondroplasia, hypochondroplasia, and thanatophoric dysplasia. J Clin Endocrinol Metab. 2015 Feb; 100(2): E355–9.
Klag KA, Horton WA. Advances in treatment of achondroplasia and osteoarthritis. Hum Mol Genet. 2016 Apr 15; 25(R1): R2–8.
Savarirayan R, Tofts L, Irving M, et al. SAT-LB18 A Randomized Controlled Trial of Vosoritide in Children With Achondroplasia. J Endocr Soc. 2020 May 8; 4(Suppl 1): SAT-LB18.
Hisado-Oliva A, Ruzafa-Martin A, Sentchordi L, et al. Mutations in C-natriuretic peptide (NPPC): a novel cause of autosomal dominant short stature. Genet Med. 2018 Jan; 20(1): 91–97.
Ueda Y, Hirota K, Yamauchi I, et al. Is C-type natriuretic peptide regulated by a feedback loop? A study on systemic and local autoregulatory effect. PLoS One. 2020 Oct 1; 15(10): e0240023. https://doi: 10.1371/journal.pone.0240023. eCollection 2020.
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