natriuretic-peptide--c-type and Growth-Disorders

Although studies in experimental animals show that blood levels of C-type natriuretic peptide (CNP) and its bioinactive aminoterminal propeptide (NTproCNP) are potential biomarkers of long bone growth, a lack of suitable assays and appropriate reference ranges has limited the application of CNP measurements in clinical practice. Plasma concentrations of the processed product of proCNP, NTproCNP - and to a lesser extent CNP itself - correlate with concurrent height velocity throughout all phases of normal skeletal growth, as well as during interventions known to affect skeletal growth in children. Since a change in levels precedes a measurable change in height velocity during interventions, measuring NTproCNP may have predictive value in clinical practice. Findings from a variety of genetic disorders affecting CNP signaling suggest that plasma concentrations of both peptides may be helpful in diagnosis, provided factors such as concurrent height velocity, feedback regulation of CNP, and differential changes in peptide clearance are considered when interpreting values. An improved understanding of factors affecting plasma levels, and the availability of commercial kits enabling accurate measurement using small volumes of plasma, can be expected to facilitate potential applications in growth disorders including genetic causes -affecting the CNP signaling pathway.

Topics: Biomarkers; Bone Development; Child; Child, Preschool; Female; Growth Disorders; Humans; Male; Natriuretic Peptide, C-Type; Signal Transduction

Besides growth hormone, several pharmaceutical products have been investigated for efficacy and safety in increasing short term growth or adult height. Short-term treatment with testosterone esters in boys with constitutional delay of growth and puberty is efficacious in generating secondary sex characteristics and growth acceleration. The addition of oxandrolone to growth hormone (GH) in Turner syndrome has an additive effect on adult height gain. Treatment with GnRH analogs is the established treatment of central precocious puberty, and its addition to GH therapy appears effective in increasing adult height in GH deficient children, and possibly short children born SGA or with SHOX deficiency, who are still short at pubertal onset. Aromatase inhibitors appear effective in several rare disorders, but their value in increasing adult height in early pubertal boys with GH deficiency or idiopathic short stature is uncertain. A trial with a C-natriuretic peptide analog offers hope for children with achondroplasia.

Topics: Achondroplasia; Androgens; Aromatase Inhibitors; Dwarfism, Pituitary; Gonadotropin-Releasing Hormone; Growth Disorders; Human Growth Hormone; Humans; Natriuretic Agents; Natriuretic Peptide, C-Type; Oxandrolone; Puberty, Precocious; Recombinant Proteins; Testosterone; Turner Syndrome

Natriuretic peptides are a family of structurally related peptides with different distinct biological effects. C-type natriuretic peptide (CNP)-mediated signaling is important for endochondral ossification and intervenes in the control of chondrocyte maturation by regulating the balance between proliferation and terminal differentiation. CNP is encoded by the NPPC gene on human chromosome 2 for which, so far, no mutations have been described in humans. Recently, two independent articles reported the description of 3 patients with a similar clinical phenotype characterized by the presence of skeletal anomalies and overgrowth. In all 3 cases, the clinical picture was associated with the presence of a balanced translocation involving chromosome 2 and causing overexpression of the NPPC gene and an increased plasma concentration of its product, CNP. Transcriptional dysregulation of NPPC has been ascribed to the separation of the gene unit from the long-range regulatory element with a transcriptional silencing effect on its expression and CNP overproduction has been correlated to the skeletal overgrowth phenotype observed.

Topics: Animals; Bone Development; Bone Diseases; Growth Disorders; Humans; Natriuretic Peptide, C-Type; Phenotype

To explore the value of amino-terminal propeptide of C-type natriuretic peptide (NTproCNP) in evaluating the effectiveness of therapy with recombinant human growth hormone (rhGH) in patients with idiopathic short stature (ISS) and isolated growth hormone deficiency (IGHD).. Forty-eight prepubertal children (IGHD = 25, ISS = 23) treated for at least 1 year with rhGH were included. Insulin growth factor-1 (IGF-I) and NTproCNP serum levels were measured before starting treatment and again 6 months later. Twelve months after starting treatment, all patients were assessed and annual growth velocity (GV), height standard deviation score (HTSDS), and gain HTSDS (deltaHTSDS) were recorded.. In the GHD group, positive relationships between GV and change of IGF-I(SDS) (deltaIGF-I(SDS)), GV and change of NTproCNP concentrations (deltaNTproCNP) were found. GH peak value was also positively associated with IGF-I(SDS) and NTproCNP before therapy and deltaIGF-I(SDS) and deltaNTproCNP were positively associated. In the ISS group, GV was associated with only deltaNTproCNP.. NTproCNP is a novel biomarker of growth as levels increase during growth-promoting treatment. Furthermore, IGF-I is also valuable in evaluating the efficacy of rhGH therapy in short stature patients.

Topics: Biomarkers; Body Height; Child; Drug Monitoring; Female; Growth Disorders; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Male; Natriuretic Peptide, C-Type; Pilot Projects

Human patients with mutations within

Topics: Achondroplasia; Animals; Female; Growth Disorders; Humans; Mammals; Mice; Natriuretic Peptide, C-Type; Pregnancy; Zebrafish

Evidence from genetic disorders of CNP signalling suggests that plasma concentrations of CNP are subject to feedback regulation. In subjects with Achondroplasia (Ach), CNP intracellular activity is suppressed and plasma concentrations are raised but the therapeutic impact of exogenous CNP agonists on endogenous CNP is unknown. In this exploratory dose finding and extension study of 28 Ach children receiving Vosoritide over a 5 year period of treatment, endogenous CNP production was assessed using measurements of plasma aminoterminal proCNP (NTproCNP) adjusted for age and sex and normalised as standard deviation score (SDS), and then related to skeletal growth. Before treatment NTproCNP SDS was raised. Within the first 3 months of accelerating growth, levels were significantly reduced. Across the 5 years of sustained growth, levels varied widely and were markedly increased in some subjects during adolescence. Plasma NTproCNP was suppressed at 4 h post-injection in proportion to the prevailing level of hormone resistance as reflected by SDS before injection. We conclude CNP remains subject to regulation during growth promoting doses of Vosoritide. Fall in CNP during accelerating growth is consistent with an indirect feedback whereas the fall at 4 h is likely to be a direct effect from removal of intra cellular CNP resistance.

Topics: Achondroplasia; Adolescent; Bone and Bones; Bone Development; Child; Child, Preschool; Feedback; Female; Growth Disorders; Humans; Male; Natriuretic Peptide, C-Type; Time Factors; Treatment Outcome

Growth impairment in mucopolysaccharidoses (MPSs) is an unresolved issue as it is resistant to enzyme replacement therapy (ERT) and growth hormone therapy. C-type natriuretic peptide (CNP) is a promising agent that has growth-promoting effects. Here we investigate the effects of CNP on growth impairment of MPSs using Gusbmps-2J mice, a model for MPS type VII, with combination therapy of CNP and ERT by hydrodynamic gene delivery. Although monotherapies were not sufficient to restore short statures of treated mice, combination therapy resulted in successful restoration. The synergistic effects of CNP and ERT were not only observed in skeletal growth but also in growth plates. ERT reduced cell swelling in the resting zone and increased cell number by accelerating proliferation or inhibiting apoptosis. CNP thickened the proliferative and hypertrophic zones. Regarding changes in the bone, ERT restored bone sclerosis through decreased bone formation and increased bone resorption, and CNP did not adversely affect this process. In addition, improvement of joint deformation by ERT was suggested by analyses of joint spaces and articular cartilage. CNP additively provided restoration of the short stature of MPS VII mice in combination with ERT, which improved abnormalities of growth plates and bone metabolism.

Topics: Animals; Cartilage, Articular; Enzyme Replacement Therapy; Genetic Therapy; Glucuronidase; Growth Disorders; Growth Plate; Mice, Inbred C57BL; Mice, Transgenic; Mucopolysaccharidosis VII; Natriuretic Peptide, C-Type

Cardio-facio-cutaneous (CFC) syndrome, a genetic disorder caused by germline mutations in BRAF, KRAS, MAP2K1 and MAP2K2, is characterized by growth retardation, heart defects, dysmorphic facial appearance and dermatologic abnormalities. We have previously reported that knock-in mice expressing the CFC syndrome-associated mutation, Braf Q241R, showed growth retardation because of gastrointestinal dysfunction. However, other factors associated with growth retardation, including chondrogenesis and endocrinological profile, have not been examined. Here, we show that 3- and 4-week-old BrafQ241R/+ mice have decreased body weight and length, as well as reduced growth plate width in the proximal tibiae. Furthermore, proliferative and hypertrophic chondrocyte zones of the growth plate were reduced in BrafQ241R/+ mice compared with Braf+/+ mice. Immunohistological analysis revealed that extracellular signal-regulated kinase (ERK) activation was enhanced in hypertrophic chondrocytes in BrafQ241R/+ mice. In accordance with growth retardation and reduced growth plate width, decreased serum levels of insulin-like growth factor 1 (IGF-1) and IGF binding protein 3 (IGFBP-3) were observed in BrafQ241R/+ mice at 3 and 4 weeks of age. Treatment with C-type natriuretic peptide (CNP), a stimulator of endochondral bone growth and a potent inhibitor of the FGFR3-RAF1-MEK/ERK signaling, increased body and tail lengths in Braf+/+ and BrafQ241R/+ mice. In conclusion, ERK activation in chondrocytes and low serum IGF-1/IGFBP-3 levels could be associated with the growth retardation observed in BrafQ241R/+ mice. Our data also suggest that CNP is a potential therapeutic target in CFC syndrome.

Topics: Animals; Chondrocytes; Disease Models, Animal; Ectodermal Dysplasia; Facies; Failure to Thrive; Germ-Line Mutation; Growth Disorders; Heart Defects, Congenital; Humans; Insulin-Like Growth Factor I; MAP Kinase Kinase 1; MAP Kinase Kinase 2; MAP Kinase Signaling System; Mice; Mice, Inbred ICR; Mutation; Natriuretic Peptide, C-Type; Proto-Oncogene Proteins B-raf

Growth retardation is an important side effect of glucocorticoid (GC)-based drugs, which are widely used in various preparations to treat many pediatric diseases. We investigated the therapeutic effect of exogenous CNP-53, a stable molecular form of intrinsic CNP, on a mouse model of GC-induced growth retardation. We found that CNP-53 successfully restored GC-induced growth retardation when both dexamethasone (DEX) and CNP-53 were injected from 4 to 8 weeks old. Notably, CNP-53 was not effective during the first week. From 4 to 5 weeks old, neither CNP-53 in advance of DEX, nor high-dose CNP-53 improved the effect of CNP. Conversely, when CNP-53 was started at 5 weeks old, final body length at 8 weeks old was comparable to that when CNP-53 was started at 4 weeks old. As for the mechanism of resistance to the CNP effect, DEX did not impair the production of cGMP induced by CNP. CNP reduced Erk phosphorylation even under treatment with DEX, while CNP did not changed that of p38 or GSK3β. Collectively, the effect of CNP-53 on GC-induced growth retardation is dependent on age in a mouse model, suggesting adequate and deliberate use of CNP would be effective for GC-induced growth retardation in clinical settings.

Topics: Animals; Dexamethasone; Disease Models, Animal; Glucocorticoids; Glycogen Synthase Kinase 3 beta; Growth Disorders; Humans; MAP Kinase Signaling System; Mice; Natriuretic Peptide, C-Type; p38 Mitogen-Activated Protein Kinases

Glucocorticoids are widely used for treating autoimmune conditions or inflammatory disorders. Long-term use of glucocorticoids causes impaired skeletal growth, a serious side effect when they are used in children. We have previously demonstrated that C-type natriuretic peptide (CNP) is a potent stimulator of endochondral bone growth. In this study, we investigated the effect of CNP on impaired bone growth caused by glucocorticoids by using a transgenic mouse model with an increased circulating CNP level. Daily administration of a high dose of dexamethasone (DEX) to 4-week-old male wild-type mice for 4weeks significantly shortened their naso-anal length, which was restored completely in DEX-treated CNP transgenic mice. Impaired growth of the long bones and vertebrae by DEX was restored to a large extent in the CNP transgenic background, with recovery in the narrowed growth plate by increased cell volume, whereas the decreased proliferation and increased apoptosis of the growth plate chondrocytes were unaffected. Trabecular bone volume was not changed by DEX treatment, but decreased significantly in a CNP transgenic background. In young male rats, the administration of high doses of DEX greatly decreased N-terminal proCNP concentrations, a marker of CNP production. In organ culture experiments using fetal wild-type murine tibias, longitudinal growth of tibial explants was inhibited by DEX but reversed by CNP. These findings now warrant further study of the therapeutic potency of CNP in glucocorticoid-induced bone growth impairment.

Topics: Animals; Bone Development; Disease Models, Animal; Glucocorticoids; Growth Disorders; Humans; Male; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Transgenic; Natriuretic Peptide, C-Type; Rats; X-Ray Microtomography

Overexpression of the C-type natriuretic peptide, encoded by the NPPC gene in 2q37.1, was recently reported in a patient presenting an overgrowth phenotype and a balanced t(2;7)(q37.1;q21.3) translocation. We present clinical, cytogenetic, and molecular data from two additional patients carrying balanced translocations involving the same 2q37.1 chromosome band and chromosomes 8 and 13, respectively. The clinical phenotype of these patients is very similar to the first patient described. In addition to the overgrowth syndrome, there is evidence of generalized cartilage dysplasia. In these two new cases, we found overexpression of NPPC, confirming that this unusual overgrowth phenotype in humans is due to the overexpression of this gene. The involvement of three different chromosomes and a cluster of breakpoints around the NPPC gene suggests that the overexpression of this gene in translocation patients could be due to its separation from a negative regulatory element located on chromosome 2, which would constitute a previously undescribed mutational mechanism.

Topics: Child; Child, Preschool; Chromosome Breakage; Chromosomes, Human, Pair 2; Chromosomes, Human, Pair 7; Gene Expression Regulation; Growth Disorders; Humans; In Situ Hybridization, Fluorescence; Karyotyping; Male; Natriuretic Peptide, C-Type; Phenotype; Reverse Transcriptase Polymerase Chain Reaction; Translocation, Genetic