The Local CNP/GC-B system in growth plate is responsible for physiological endochondral bone growth

Nakao, Kazumasa; Osawa, Kenji; Yasoda, Akihiro; Yamanaka, Sadanori; Fujii, Toshihito; Kondo, Eri; Koyama, Noriaki; Kanamoto, Naotetsu; Miura, Masako; Kuwahara, Koichiro; Akiyama, Haruhiko; Bessho, Kazuhisa; Nakao, Kazuwa

doi:10.1038/srep10554

Cited by 68 publications

(72 citation statements)

References 47 publications

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“…Together with evidence of a venoarterial CNP gradient across dense bone tissues in growing lambs [19], these findings suggest not only that growth plate tissues make a major contribution to circulating levels of NTproCNP, but also that plasma concentrations are in turn impacted by the activity of these tissues. This conclusion aligns with recent findings from studies using genetic modifications showing that the local (paracrine) CNP signaling pathway in growth plates is responsible for physiological endochondral bone growth [26]. …”

Section: Evidence That Plasma Cnp Products Correlate With Skeletal Grsupporting

confidence: 78%

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

2018

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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.

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Section: Evidence That Plasma Cnp Products Correlate With Skeletal Grsupporting

confidence: 78%

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

2018

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“…13,21 Therefore, to investigate the potential role of GC-B expressed on VSMCs in mediating blood pressure regulation by endothelium-derived CNP, we generated and analyzed GC-B smcKO mice. 8,22,23 We confirmed deletion of the allele using genomic DNA from tail samples ( Figure 4A) and found that expression of GC-B mRNA was, respectively, ≈90% and ≈80% lower in aortas and mesenteric arteries from GC-B smcKO mice than from their control Npr2 flox/flox littermates ( Figure 4B and 4C). Whole body weights and the weights of the heart and kidneys did not differ between GC-B smcKO mice and their control littermates (Table S3).…”

Section: Generation Of Vascular Smooth Muscle Cellspecific Gc-b Knockmentioning

confidence: 50%

“…8,16,17 Using samples from the tails of CNP ecKO (Nppc flox/flox ; Tie2-Cre Tg) mice, we confirmed Cre-mediated recombination of the Nppc-floxed allele ( Figure 1A). In CD31 + pulmonary microvascular endothelial cells collected from the lungs of CNP ecKO mice, we confirmed that CNP mRNA levels were reduced to <10% of that in cells from the control mice (Nppc flox/flox ; Figure 1B).…”

Section: Generation Of Endothelial Cell-specific Cnp Knockout Micementioning

confidence: 62%

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Endothelium-Derived C-Type Natriuretic Peptide Contributes to Blood Pressure Regulation by Maintaining Endothelial Integrity

et al. 2017

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We previously reported the secretion of C-type natriuretic peptide (CNP) from vascular endothelial cells and proposed the existence of a vascular natriuretic peptide system composed of endothelial CNP and smooth muscle guanylyl cyclase-B (GC-B), the CNP receptor, and involved in the regulation of vascular tone, remodeling, and regeneration. In this study, we assessed the functional significance of this system in the regulation of blood pressure in vivo using vascular endothelial cell–specific CNP knockout and vascular smooth muscle cell–specific GC-B knockout mice. These mice showed neither the skeletal abnormality nor the early mortality observed in systemic CNP or GC-B knockout mice. Endothelial cell–specific CNP knockout mice exhibited significantly increased blood pressures and an enhanced acute hypertensive response to nitric oxide synthetase inhibition. Acetylcholine-induced, endothelium-dependent vasorelaxation was impaired in rings of mesenteric artery isolated from endothelial cell–specific CNP knockout mice. In addition, endothelin-1 gene expression was enhanced in pulmonary vascular endothelial cells from endothelial cell–specific CNP knockout mice, which also showed significantly higher plasma endothelin-1 concentrations and a greater reduction in blood pressure in response to an endothelin receptor antagonist than their control littermates. By contrast, vascular smooth muscle cell–specific GC-B knockout mice exhibited blood pressures similar to control mice, and acetylcholine-induced vasorelaxation was preserved in their isolated mesenteric arteries. Nonetheless, CNP-induced acute vasorelaxation was nearly completely abolished in mesenteric arteries from vascular smooth muscle cell–specific GC-B knockout mice. These results demonstrate that endothelium-derived CNP contributes to the chronic regulation of vascular tone and systemic blood pressure by maintaining endothelial function independently of vascular smooth muscle GC-B.

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“…Mice or humans that overexpress CNP or activate natriuretic peptide receptor 2 (Npr2; guanylyl cyclase B) have a skeletal overgrowth phenotype ( Fig. 2; Yasoda et al 2004;Bocciardi et al 2007;Hannema et al 2013;Miura et al 2014), while mice that lack CNP (Nppc −/− ) or humans with heterozygous mutations in NPR2 exhibit skeletal dwarfism (Tsuji and Kunieda 2005;Nakao et al 2015).…”

Section: Therapeutic Strategies In Achondroplasiamentioning

confidence: 99%

Fibroblast growth factor signaling in skeletal development and disease

2015

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Fibroblast growth factor (FGF) signaling pathways are essential regulators of vertebrate skeletal development. FGF signaling regulates development of the limb bud and formation of the mesenchymal condensation and has key roles in regulating chondrogenesis, osteogenesis, and bone and mineral homeostasis. This review updates our review on FGFs in skeletal development published in Genes & Development in 2002, examines progress made on understanding the functions of the FGF signaling pathway during critical stages of skeletogenesis, and explores the mechanisms by which mutations in FGF signaling molecules cause skeletal malformations in humans. Links between FGF signaling pathways and other interacting pathways that are critical for skeletal development and could be exploited to treat genetic diseases and repair bone are also explored.

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The Local CNP/GC-B system in growth plate is responsible for physiological endochondral bone growth

Cited by 68 publications

References 47 publications

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

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

Endothelium-Derived C-Type Natriuretic Peptide Contributes to Blood Pressure Regulation by Maintaining Endothelial Integrity

Fibroblast growth factor signaling in skeletal development and disease

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