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Lead Acetate-Injected Mice is an Animal Model for Extrapolation of Calcifying Response to Humans Due to Low Involvement of Bone Resorption

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Abstract

Vascular calcification affects the prognosis of patients with renal failure. Bisphosphonates are regarded as candidate anti-calcifying drugs because of their inhibitory effects on both calcium-phosphate aggregation and bone resorption. However, calcification in well-known rodent models is dependent upon bone resorption accompanied by excessive bone turnover, making it difficult to estimate accurately the anti-calcifying potential of drugs. Therefore, models with low bone resorption are required to extrapolate anti-calcifying effects to humans. Three bisphosphonates (etidronate, alendronate, and FYB-931) were characterised for their inhibitory effects on bone resorption in vivo and calcium-phosphate aggregation estimated by calciprotein particle formation in vitro. Then, their effects were examined using two models inducing ectopic calcification: the site where lead acetate was subcutaneously injected into mice and the transplanted, aorta obtained from a donor rat. The inhibitory effects of bisphosphonates on bone resorption and calcium-phosphate aggregation were alendronate > FYB-931 > etidronate and FYB-931 > alendronate = etidronate, respectively. In the lead acetate-induced model, calcification was most potently suppressed by FYB-931, followed by alendronate and etidronate. In the aorta-transplanted model, only FYB-931 suppressed calcification at a high dose. In both the models, no correlation was observed between calcification and bone resorption marker, tartrate-resistant acid phosphatase (TRACP). Results from the lead acetate-induced model showed that inhibitory potency against calcium-phosphate aggregation contributed to calcification inhibition. The two calcification models, especially the lead acetate-induced model, may be ideal for the extrapolation of calcifying response to humans because of calcium-phosphate aggregation rather than bone resorption as its mechanism.

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Acknowledgements

We thank Dr. Koji Matsumoto, and Ms. Noriko Chikamatsu in FUJI YAKUHIN CO., LTD. for their assistance in the in vivo evaluation.

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The authors are employees of FUJI YAKUHIN CO., LTD.

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  1. Research Laboratories 2, FUJI YAKUHIN CO., LTD., 636-1 Iidashinden, Nishi-ku, Saitama, Saitama Prefecture, 331-0068, Japan

    Shota Morikane, Koichi Ishida, Naoki Ashizawa, Tetsuya Taniguchi, Masaya Matsubayashi, Naoki Kurita & Takashi Iwanaga

  2. Research Laboratories 1, FUJI YAKUHIN CO., LTD., 3936-2 Sashiogi, Nishi-ku, Saitama, Saitama Prefecture, 331-0047, Japan

    Seiichi Kobashi

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  1. Shota Morikane
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Contributions

Participated in research design: Shota Morikane, Koichi Ishida, Naoki Ashizawa, Naoki Kurita, Seiichi Kobashi and Takashi Iwanaga. Conducted experiments: Shota Morikane, Koichi Ishida and Naoki Ashizawa. Wrote or contributed to the writing of the manuscript: Shota Morikane, Naoki Ashizawa, Koichi Ishida, Masaya Matsubayashi, and Tetsuya Taniguchi. All authors read and approved the final manuscript.

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Correspondence to Shota Morikane.

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Shota Morikane, Koichi Ishida, Naoki Ashizawa, Tetsuya Taniguchi, Masaya Matsubayashi, Naoki Kurita, Seiichi Kobashi and, Takashi Iwanaga have no conflict of interest directly relevant to the content of this manuscript.

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The animal experiments were approved by the Animal Care Utilisation Committee of FUJI YAKUHIN Research Laboratories, which is accredited by the Japan Health Sciences Foundation. All procedures were performed in compliance with ARRIVE and the National Guidelines for Animal Care and Use.

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Morikane, S., Ishida, K., Ashizawa, N. et al. Lead Acetate-Injected Mice is an Animal Model for Extrapolation of Calcifying Response to Humans Due to Low Involvement of Bone Resorption. Calcif Tissue Int (2024). https://doi.org/10.1007/s00223-024-01245-w

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