Читать книгу Nutrition and Growth - Группа авторов - Страница 17

Hirota K¹, Furuya M^2,3, Morozumi N², Yoshikiyo K², Yotsumoto T², Jindo T², Nakamura R², Murakami K¹, Ueda Y¹, Hanada T², Sade H², Yoshida S², Enomoto K², Kanai Y¹, Yamauchi I¹, Yamashita T¹, Ueda-Sakane Y¹, Fujii T¹, Yasoda A¹, Inagaki N¹

¹Department of Diabetes, Endocrinology and Nutrition, Kyoto University Graduate School of Medicine, Kyoto, Japan; ²Asubio Pharma Co. Ltd. Kobe, Japan; ³Medical Innovation Center, Kyoto University Graduate School of Medicine, Kyoto, Japan

PLoS One 2018; 13:e0204172

Background: 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.

Methods: 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 4-week old CNP-KO and littermate wild type (WT) rats.

Results: 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.

Conclusions: 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.

Unmodified reproduction. This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/deed.en)

Comments

Several manuscripts reported on the use of plasma C-type natriuretic peptide (CNP) as a potential therapeutic and/or diagnostic tool in growth failure including achondroplasia. CNP and its bioinactive aminoterminal propeptide (NTproCNP) are potential biomarkers of long bone growth. However, lack of suitable assays and appropriate reference ranges limits the application of CNP measurements in clinical practice, for example, predicting height velocity during interventions known to affect skeletal growth in children [5]. Therapeutic use of CNP-53, an endogenous form of CNP consisting of 53 amino acids, was studied in CNP knockout rats. Continuous subcutaneous infusion of CNP-53 significantly, and in a dose-dependent manner, stimulated skeletal growth. It normalized the length of long bones and the growth plate thickness and prevented growth plate closure. These data suggest that CNP-53, or its analog, may have the potential to promote growth and to prevent early growth plate closure in the short stature [6]. Another novel therapeutic agent for skeletal growth, a chimeric peptide composed of CNP (1–22) and human ghrelin (12–28, E17D), was studied. Especially, sc infusion stimulated skeletal growth in rats. Authors propose that pharmaceutical formulation approaches for sustained-release dosage forms to allow chronic exposure to ASB20123 might be suitable to ensure drug effectiveness and safety [7]. These studies provide alternative approaches to achondroplasia treatment that is already in the final clinical trial phases [8].

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