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
prolekare.web.journal.doi_sk:
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 – Biochemistry – Anatomy – Medicine and health sciences – Pathology and laboratory medicine – Diagnostic medicine – Signs and symptoms – Biomarkers – Biological tissue – Connective tissue – Musculoskeletal system – Skeleton – Toxicology – Cartilage – Toxicity – Bone – Growth plate – Bone density – Necrosis
Zdroje
1. Ornitz DM, Legeai-Mallet L. Achondroplasia: Development, pathogenesis, and therapy. Dev Dyn. 2017;246(4): 291–309. doi: 10.1002/dvdy.24479 27987249
2. Krejci P, Masri B, Fontaine V, Mekikian PB, Weis M, Prats H, et al. Interaction of fibroblast growth factor and C-natriuretic peptide signaling in regulation of chondrocyte proliferation and extracellular matrix homeostasis. J Cell Sci. 2005;118: 5089–5100 16234329
3. Chusho H, Tamura N, Ogawa Y, Yasoda A, Suda M, Miyazawa T, et al. Dwarfism and early death in mice lacking C-type natriuretic peptide. Proc Natl Acad Sci. 2001;98: 4016–4021. doi: 10.1073/pnas.071389098 11259675
4. Fujii T, Hirota K, Yasoda A, Takizawa A, Morozumi N, Nakamura R, et al. Rats deficient C-type natriuretic peptide suffer from impaired skeletal growth with normal life-span. PLos One. 2018;13(3): e0194812.
5. Yotsumoto T, Morozumi N, Furuya M, Fujii T, Hirota K, Ueda Y, et al. Foramen magnum stenosis and midface hypoplasia in C-Type natriuretic peptide deficient rats and its restoration by exogenous administration of CNP-53. PLoS One 2019;14(5): e0216340.
6. Legeai-Mallet L. C-type natriuretic peptide analog as therapy for achondroplasia. Endocr Dev 2016;10(30): 98–105. doi: 10.1159/000439334
7. Lorget F, Kaci N, Peng J, Benoist-Lasselin C, Mugniery E, Oppeneer T, et al. Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia. Am J Hum Genet. 2012;91(6): 1108–1114. doi: 10.1016/j.ajhg.2012.10.014 23200862
8. Wendt DJ, Dvorak-Ewell M, Bullens S, Lorget F, Bell SM, Peng J, et al. Neutral endopeptidase-resistant C-type natriuretic peptide variant represents a new therapeutic approach for treatment of fibroblast growth factor receptor 3-related dwarfism. J Pharmacol Exp Ther. 2015;353(1): 132–149. doi: 10.1124/jpet.114.218560 25650377
9. Morozumi N, Hanada T, Habara H, Yamaki A, Furuya M, Nakatsuka T, et al. The role of C-terminal part of ghrelin in pharmacokinetic profile and biological activity in rats. Peptides. 2011; 32: 1001–1007. doi: 10.1016/j.peptides.2011.01.021 21291937.
10. Morozumi N, Sato S, Yoshida S, Yamaki A, Furuya F, Inomata N, et al. A new strategy for metabolic stabilization of motilin using the C-terminal part of ghrelin. Peptides. 2012; 33:279–284. doi: 10.1016/j.peptides.2012.01.010 22286034.
11. Morozumi N, Sato S, Yoshida S, Harada Y, Furuya M, Minamitake Y, et al. Design and evaluation of novel natriuretic peptide derivatives with improved pharmacokinetic and pharmacodynamic properties. Peptides. 2017; 97:16–21. doi: 10.1016/j.peptides.2017.09.008 28899838.
12. Jean L, Mizon C, Larsen WJ, Mizon J, Salier JP. Unmasking a hyaluronan-binding site of the BX(7)B type in the H3 heavy chain of the inter-alpha-inhibitor family. Eur J Biochem. 2001; 268(3):544–553. 11168393
13. Morozumi N, Yotsumoto T, Yamaki A, Yoshikiyo K, Yoshida S, Nakamura R, et al. ASB20123: A novel C-type natriuretic peptide derivatives for the treatment of growth failure and dwarfism. PLos One 2019; 14(2): e0212680 https://doi.org/10.1371/journal.pone.0212680 30794654.
14. Komatsu Y, Nakao K, Suga S, Ogawa Y, Mukoyama M, Arai H, et al. C-type natriuretic peptide (CNP) in rats and humans. Endocrinology. 1991;129(2): 1104–1106. 1855454
15. Potter LR. Regulation and therapeutic targeting of peptide-activated receptor guanylyl cyclases. Pharmacol Ther. 2011;130(1): 71–82. doi: 10.1016/j.pharmthera.2010.12.005 21185863
16. Chang CY, Rosenthal DI, Mitchell DM, Handa A, Kattapuram SV, Huang AJ. Imaging findings of metabolic bone disease. Radiographics. 2016;36(6): 1871–1887. 27726750
17. Jawetz ST, Shah PH, Potter HG. Imaging of physeal injury: overuse. Sports Health. 2015;7(2): 142–153. doi: 10.1177/1941738114559380 25984260
18. Sims D, Onambele-Pearson G, Burden A, Payton C, Morse C. Whole-body and segmental analysis of body composition in adult males with achondroplasia using dual X-ray absorptiometry. PLos One, 2019;14(3): e0213806. https://doi.org/10.1371/journal.pone.0213806 30889196.
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