Research Article: Safety assessment of a novel C-type natriuretic peptide derivative and the mechanism of bone- and cartilage-specific toxicity

Date Published: September 11, 2019

Publisher: Public Library of Science

Author(s): Takafumi Yotsumoto, Naomi Morozumi, Ryuichi Nakamura, Toshimasa Jindo, Mayumi Furuya, Yasuyuki Abe, Tomonari Nishimura, Hiroaki Maeda, Hiroyuki Ogasawara, Yoshiharu Minamitake, Kenji Kangawa, Michael Bader.

http://doi.org/10.1371/journal.pone.0218229

Abstract

ASB20123, a C-type natriuretic peptide/ghrelin chimeric peptide, was designed as a novel peptide and demonstrated full agonistic activity for natriuretic-peptide receptor B and a significantly longer half-life in plasma compared with the native peptide. We researched the toxicological profile of ASB20123, the correlation between the morphological change of the epiphyseal plate and bone and cartilage toxicity, and biomarkers to detect the toxicity. ASB20123 was systemically administered to male and female rats at daily dose levels of 0.5, 1.5, and 5.0 mg/kg/day for 4 weeks. In this study, toxicity was observed as changes related to bone and cartilage tissues, and no other toxicological changes were observed in all animals. Next, ASB20123 was administered to 12-month-old rats with a little epiphyseal plate. The toxic changes related to bone and cartilage tissues were not observed in any animal with a closed epiphyseal plate, indicating that the toxic changes were triggered by the growth-accelerating effect on the bone and cartilage. Furthermore, we searched for the biomarker related to the bone and cartilage toxicity using rats treated with ASB20123 at doses of 0.005, 0.05, 0.5, and 5.0 mg/kg/day for 4 weeks. A close correlation between necrosis/fibrosis in the epiphysis and metaphysis and thickness of the epiphyseal plate in the femur was confirmed in this study. A decrease in the bone mineral density (BMD) of the femur also was associated with the appearance of bone toxicity. These results indicated that the toxicity of ASB20123 was limited to bone- and cartilage-specific changes, and these changes were triggered by an excessive growth accelerating effect. Furthermore, our data suggested that the thickness of the epiphyseal plate and BMD could be reliable biomarkers to predict bone toxicity.

Partial Text

The C-type natriuretic peptide (CNP) analog is one of the most exciting therapeutic approaches to treat achondroplasia [1]. The binding of CNP to natriuretic-peptide receptor B (NPR-B) inhibits fibroblast growth factor receptor 3 downstream signaling [2], recognized as an important regulator of endochondral bone growth [3]. We recently reported that the exogenous administration of CNP-53 has the potential to stimulate skeletal growth related to short stature, and restore the skull morphology and size of foramen magnum in CNP-KO rats [4, 5]. As a CNP derivative, a clinical trial utilizing BMN-111 is currently proceeding in pediatric patients with achondroplasia [6–8].

ASB20123 is a CNP derivative, and this peptide stimulates bone growth through proliferation and differentiation of chondrocytes [13]. In this study, ASB20123 was administered to male and female rats at daily dose levels of 0.5, 1.5, and 5.0 mg/kg/day for 4 weeks to investigate its toxicity. In this study, toxic changes were observed in the bone and cartilage tissues, and no other toxic changes were observed in all animals.

 

Source:

http://doi.org/10.1371/journal.pone.0218229

 

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