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Etelcalcetide decreases the PTH–calcium setpoint without changing maximum and minimum PTH secretion in mice with primary hyperparathyroidism

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Abstract

Introduction

Etelcalcetide binds to the extracellular domain of the calcium-sensing receptor (CaSR), while cinacalcet binds to the 7-transmembrane domain of the CaSR; however, it is unknown, whether etelcalcetide has similar effects to cinacalcet on parathyroid hormone (PTH) secretion.

Materials and methods

The PTH–calcium setpoint and maximum and minimum PTH secretion were determined using an ‘in vivo setpoint analyses.’ The PTH–calcium setpoint was obtained in a mouse model of primary hyperparathyroidism (PC) and wild-type (WT) mice, with PC mice divided into two groups. The setpoint was obtained after 7 days of etelcalcetide (3.0 mg/kg BW/day) or vehicle administration via anosmotic pump. After 7 days of crossover administration, the setpoint was obtained again. Parathyroid glands were obtained after crossover administration, and CaSR expression was analyzed by immunohistochemistry.

Results

Etelcalcetide administration significantly decreased the setpoint from 9.03 ± 0.56 mg/dL to 6.80 ± 0.28 mg/dL, which was restored to 8.81 ± 0.38 mg/dL after vehicle administration. In the second group of mice, vehicle administration did not alter the setpoint (8.84 ± 0.69 mg/dL to 8.98 ± 0.63 mg/dL), but subsequent etelcalcetide administration significantly decreased it to 7.10 ± 0.72 mg/dL. There was no significant change in maximum and minimum PTH secretion. Expression levels of parathyroid CaSR were lower in PC mice than in WT mice; however, no significant differences were observed between the two mouse groups.

Conclusion

Etelcalcetide decreased the PTH–calcium setpoint without changing maximum and minimum PTH secretion in PC mice, suggesting that like cinacalcet, etelcalcetide has calcimimetic potency.

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Acknowledgements

We gratefully thank Prof. Andrew Arnold (University of Connecticut School of Medicine) for providing us with PC mice and for engaging in in-depth discussions. We thank Ms. Emi Donoue and Mr. Keisuke Inoue (Research Support Platform of Osaka City University Graduate School of Medicine) for technical support.

Funding

This work was supported in part by a research Grant from ONO Pharmaceutical, Co., Ltd., Osaka, Japan.

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Authors and Affiliations

  1. Department of Metabolism, Endocrinology and Molecular Medicine, Osaka City University Graduate School of Medicine, 1-4-3, Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan

    Noriyuki Hayashi, Yasuo Imanishi, Tomoe Hirakawa, Ikue Kobayashi, Tomomi Tateishi, Daichi Miyaoka, Yuki Nagata, Katsuhito Mori, Tomoaki Morioka, Atsuto Inoue, Kazutsune Harada, Masaaki Inaba & Masanori Emoto

  2. ONO Pharmaceutical Co., Ltd., Osaka, Japan

    Atsuto Inoue & Kazutsune Harada

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  1. Noriyuki Hayashi
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  2. Yasuo Imanishi
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Contributions

YI designed the study and wrote the main manuscript. NH and TH contributed to the setpoint analysis, and TH and IK contributed to the immunohistochemistry experiments. TH, TT, DM, YN, and TM contributed to the acquisition, analysis, and interpretation of the data. KM, AI, KH, ME, and MI reviewed the manuscript critically for intellectual content. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Yasuo Imanishi.

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Conflict of interest

YI, KM, ME, and MI received lecture fees from ONO Pharmaceutical Co., Ltd., Osaka, Japan. AI and KH are employees of ONO Pharmaceutical Co., Ltd., Osaka, Japan. NH, TH, IK, TT, DM, YN, and TM declare no conflicts of interest.

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Hayashi, N., Imanishi, Y., Hirakawa, T. et al. Etelcalcetide decreases the PTH–calcium setpoint without changing maximum and minimum PTH secretion in mice with primary hyperparathyroidism. J Bone Miner Metab 39, 430–438 (2021). https://doi.org/10.1007/s00774-020-01169-z

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  • DOI: https://doi.org/10.1007/s00774-020-01169-z

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