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Bisphosphonate FYB-931 Prevents High Phosphate-Induced Vascular Calcification in Rat Aortic Rings by Altering the Dynamics of the Transformation of Calciprotein Particles

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Abstract

Patients with chronic kidney disease develop vascular calcification, owing to impaired calcium and phosphate metabolism. The prevention of vascular calcification is important to improve the prognosis of such patients. In this study, we investigated whether treatment with FYB-931, a novel bisphosphonate compound, prevents vascular calcification in rat aortic rings cultured in high-phosphate medium for 9 days, assessed by measurement of the calcium content and the degree of calcium deposition, visualized using von Kossa staining. The effect on the transformation of calciprotein particles (CPPs) from primary to secondary CPPs was assessed using a fluorescent probe-based flow cytometric assay. FYB-931 dose-dependently prevented high phosphate-induced aortic calcification, but failed to rapidly cause the regression of high phosphate-induced vascular calcification once it had developed. Furthermore, the treatment dose-dependently inhibited the high phosphate-induced transformation from primary to secondary CPPs. In addition, the treatment with FYB-931 prevented the transformation from primary to secondary CPPs in vitamin D3-treated rats as a model of ectopic calcification, consistent with the results from rat aortic rings. In conclusion, treatment with FYB-931 prevents high phosphate-induced rat aortic vascular calcification by altering the dynamics of CPP transformation. This finding suggests that inhibition of the transformation from primary to secondary CPPs is an important target for the prevention of vascular calcification in patients with chronic kidney disease.

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Acknowledgements

We thank Mark Cleasby, PhD from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

Funding

This work was supported by joint collaborative funding from Fuji Yakuhin Co. Ltd. (Saitama, Japan) providing drug substance of FYB-931 and research funding.

Author information

Authors and Affiliations

  1. Department of Nephrology, Wakayama Medical University, 811-1 Kimiidera, Wakayama, Wakayama, 641-8509, Japan

    Kazuki Kawakami, Masaki Ohya, Mitsuru Yashiro, Tomohiro Sonou, Shuto Yamamoto, Yuri Nakashima, Takuro Yano, Yusuke Tanaka, Takashi Shigematsu & Shin-ichi Araki

  2. Medical R&D Division, Fuji Yakuhin Co. Ltd, Laboratory 2, Iidashinden, Nishi-ku, Saitama, Saitama, 331-0068, Japan

    Koichi Ishida

  3. Medical R&D Division, Fuji Yakuhin Co. Ltd, Laboratory 1, Nishiomiya, Nishi-ku, Saitama, Saitama, 331-0078, Japan

    Seiichi Kobashi

  4. Department of Nephrology, Rinku General Medical Center, Izumisano, Osaka, 598-8577, Japan

    Takashi Shigematsu

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  1. Kazuki Kawakami
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Contributions

KK performed all the experiments and wrote the initial draft of the manuscript. MY and TS assisted with the data collection. MO and SA edited the manuscript. TS designed the study. SY, YN, TY, and YT contributed to discussion. KI and SK provided experimental resources and contributed to discussion. All the authors reviewed and contributed to the final version of the manuscript.

Corresponding author

Correspondence to Masaki Ohya.

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Conflict of interest

Masaki Ohya has received lecture fees from Kyowa Kirin Co, Ltd., Sanwa Kagaku Kenkyusho Co. Ltd. and Ono Pharmaceutical Co. Ltd. Takashi Shigematsu has received funding for the present study from Fuji Yakuhin Co. Ltd., and lecture fees from Kyowa Kirin Co. Ltd., Sanwa Kagaku Kenkyusho Co. Ltd. and Ono Pharmaceutical Co. Ltd. Shin-ichi Araki has received lecture fees from Kyowa Kirin Co. Ltd., AstraZeneca Co. Ltd. and Mitsubishi Tanabe Pharma Corporation: research grants from Kyowa Kirin Co. Ltd. and Torii Pharmaceutical Co. Ltd. Other authors state that they have no conflicts of interest. 

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Kawakami, K., Ohya, M., Yashiro, M. et al. Bisphosphonate FYB-931 Prevents High Phosphate-Induced Vascular Calcification in Rat Aortic Rings by Altering the Dynamics of the Transformation of Calciprotein Particles. Calcif Tissue Int 113, 216–228 (2023). https://doi.org/10.1007/s00223-023-01086-z

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