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

• Published in: Calcified tissue international 2024-09, Vol.115 (3), p.315-327
• Main Authors: Morikane, Shota, Ishida, Koichi, Ashizawa, Naoki, Taniguchi, Tetsuya, Matsubayashi, Masaya, Kurita, Naoki, Kobashi, Seiichi, Iwanaga, Takashi
• Format: Article
• Language: English
• Subjects: Acid phosphatase (tartrate-resistant); Alendronic acid; Animal models; Aorta; Biochemistry; Biomedical and Life Sciences; Bisphosphonates; Bone growth; Bone resorption; Bone turnover; Calcification; Calcification (ectopic); Calcium phosphates; Cell Biology; Coronary vessels; Drug development; Endocrinology; Etidronic acid; Life Sciences; Original Research; Orthopedics; Phosphate; Renal failure
• ISSN: 1432-0827; 0171-967X; 1432-0827
• DOI: 10.1007/s00223-024-01245-w

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.