Safety assessment of a novel C-type natriuretic peptide derivative and the mechanism of bone- and cartilage-specific toxicity
Autoři:
Takafumi Yotsumoto aff001; Naomi Morozumi aff001; Ryuichi Nakamura aff001; Toshimasa Jindo aff001; Mayumi Furuya aff001; Yasuyuki Abe aff001; Tomonari Nishimura aff001; Hiroaki Maeda aff001; Hiroyuki Ogasawara aff001; Yoshiharu Minamitake aff001; Kenji Kangawa aff003
Působiště autorů:
Asubio Pharma Co., Ltd., Kobe, Japan
aff001; Daiichi Sankyo Co., Ltd., Tokyo, Japan
aff002; National Cerebral and Cardiovascular Center Research Institute, Osaka, Japan
aff003
Vyšlo v časopise:
PLoS ONE 14(9)
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pone.0218229
Souhrn
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.
Klíčová slova:
Biology and life sciences – Anatomy – Biological tissue – Connective tissue – Cartilage – Musculoskeletal system – Toxicology – Toxicity – Biochemistry – Biomarkers – Medicine and health sciences – Bone – Growth plate – Bone density – Skeleton – Pathology and laboratory medicine – Necrosis – Diagnostic medicine – Signs and symptoms
Zdroje
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PLOS One
2019 Číslo 9
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