Circulating osteocrin stimulates bone growth by limiting C-type natriuretic peptide clearance

Kanai, Yugo; Yasoda, Akihiro; Mori, Keita; Watanabe-Takano, Haruko; Nagai‐Okatani, Chiaki; Yamashita, Yui; Hirota, Keisho; Ueda, Yohei; Yamauchi, Ichiro; Kondo, Eri; Yamanaka, Sadanori; Sakane, Yoriko; Nakao, Kazumasa; Fujii, Toshihito; Yokoi, Hideki; Minamino, Naoto; Mukoyama, Masashi; Mochizuki, Naoki; Inagaki, Nobuya

doi:10.1172/jci94912

Cited by 46 publications

(52 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Notably, the effects of CNP-53 were more prominent in the CNP-KO rats compared with those in the WT rats. This phenomenon might at least in part owe the fact that the mRNA for osteocrin, a natural NPR-C ligand [ 19 ], was increased in the growth plates of CNP KO rats compared to WT rats, whereas there were no differences in mRNA expressions for NPR-B and NPR-C between genotypes ( Fig 8 ), even though the lines and the gender of CNP KO rats used in administration experiments and RT-PCR analyses were different (homozygous Δ 11 deleted female and homozygous Δ 774 deleted male, see “ Materials and methods ”); the increased osteocrin in CNP-KO rats might prevent the degradation of exogenous CNP-53 and contribute to the enhanced skeletal growth in these rats compared with WT rats [ 25 ]. Since the plasma CNP concentration was similar in CNP-KO and WT rats after four weeks of CNP-53 infusion, the increase of CNP-53 at growth plate through the local regulation by osteocrin may lead to the stronger effect on skeletal growth in CNP-KO rats.…”

Section: Discussionmentioning

confidence: 99%

Exogenous C-type natriuretic peptide restores normal growth and prevents early growth plate closure in its deficient rats

et al. 2018

Self Cite

View full text Add to dashboard Cite

Signaling by C-type natriuretic peptide (CNP) and its receptor, natriuretic peptide receptor-B, is a pivotal stimulator of endochondral bone growth. We recently developed CNP knockout (KO) rats that exhibit impaired skeletal growth with early growth plate closure. In the current study, we further characterized the phenotype and growth plate morphology in CNP-KO rats, and the effects of exogenous CNP in rats. We used CNP-53, an endogenous form of CNP consisting of 53 amino acids, and administered it for four weeks by continuous subcutaneous infusion at 0.15 or 0.5 mg/kg/day to four-week old CNP-KO and littermate wild type (WT) rats. We demonstrated that CNP-KO rats were useful as a reproducible animal model for skeletal dysplasia, due to their impairment in endochondral bone growth. There was no significant difference in plasma bone-turnover markers between the CNP-KO and WT rats. At eight weeks of age, growth plate closure was observed in the distal end of the tibia and the calcaneus of CNP-KO rats. Continuous subcutaneous infusion of CNP-53 significantly, and in a dose-dependent manner, stimulated skeletal growth in CNP-KO and WT rats, with CNP-KO rats being more sensitive to the treatment. CNP-53 also normalized the length of long bones and the growth plate thickness, and prevented growth plate closure in the CNP-KO rats. Using organ culture experiment of fetal rat tibia, gene set enrichment analysis indicated that CNP might have a negative influence on mitogen activated protein kinase signaling cascades in chondrocyte. Our results indicated that CNP-KO rats might be a valuable animal model for investigating growth plate physiology and the mechanism of growth plate closure, and that CNP-53, or its analog, may have the potential to promote growth and to prevent early growth plate closure in the short stature.

show abstract

Section: Discussionmentioning

confidence: 99%

Exogenous C-type natriuretic peptide restores normal growth and prevents early growth plate closure in its deficient rats

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…CNP is cleared by the NPR-C receptor and blocking that receptor increases circulating CNP. A recent study used a transgenic mouse overexpressing osteonecrin, a NPR-C ligand without natriuretic activity, and successfully demonstrated increased bone growth in these mice [41]. No report has been published on an achondroplasia mouse model.…”

Section: Other Debated Approaches-past and Presentmentioning

confidence: 99%

New developments in the management of achondroplasia

Högler

Ward

2020

Wien Med Wochenschr

View full text Add to dashboard Cite

Achondroplasia is the most common form of disproportionate short stature. A dominantly inherited FGFR3 mutation permanently activates the fibroblast growth factor receptor 3 (FGFR3) and its downstream mitogen-activated protein kinase (MAPK) signalling pathway. This inhibits chondrocyte differentiation and puts a break on growth plate function, in addition to causing serious medical complications such as foramen magnum and spinal stenosis and upper airway narrowing. A great deal has been learned about complications and consequences of FGFR3 activation and management guidance is evolving aimed to reduce the increased mortality and morbidity in this condition, particularly deaths from spinal cord compression and sleep apnoea in infants and small children. To date, no drugs are licensed for treatment of achondroplasia. Here, we report on the various substances in the drug development pipeline which target elements in molecular disease mechanism such as FGF (fibroblast growth factor) ligands, FGFR3, MAPK signalling as well as the C-type natriuretic peptide receptor NPR-B (natriuretic peptide receptor B).

show abstract

“…The same directional change in ratio for ANP and BNP would also be expected. On the other hand, mutations causing a gain-of-function mutation in osteocrin (an endogenous ligand with strong affinity for NPR3 ) would be expected to have the opposite impact, and a phenotype similar to that of the LOF mutation in NPR3 [72]. In view of the limited knowledge of mechanisms underlying many growth disorders, it is likely that measurements of CNP products will be revealing in some areas and possibly lead to novel treatments.…”

Section: Plasma Cnp Products and Genetic Disorders Of Growthmentioning

confidence: 99%

Plasma C-Type Natriuretic Peptide: Emerging Applications in Disorders of Skeletal Growth

2018

View full text Add to dashboard Cite

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.

show abstract

Circulating osteocrin stimulates bone growth by limiting C-type natriuretic peptide clearance

Cited by 46 publications

References 32 publications

Exogenous C-type natriuretic peptide restores normal growth and prevents early growth plate closure in its deficient rats

Exogenous C-type natriuretic peptide restores normal growth and prevents early growth plate closure in its deficient rats

New developments in the management of achondroplasia

Plasma C-Type Natriuretic Peptide: Emerging Applications in Disorders of Skeletal Growth

Contact Info

Product

Resources

About