血管钙化影响肾衰竭患者的预后。双膦酸盐由于其对磷酸钙聚集和骨吸收的抑制作用而被认为是候选的抗钙化药物。然而,众所周知的啮齿动物模型中的钙化取决于骨吸收,并伴有过度的骨转换,这使得很难准确估计药物的抗钙化潜力。因此,需要具有低骨吸收的模型来推断对人类的抗钙化作用。三种双膦酸盐(依替膦酸盐,阿仑膦酸盐,和FYB-931)的特征在于它们对体内骨吸收和体外钙蛋白颗粒形成估计的磷酸钙聚集的抑制作用。然后,使用两种诱导异位钙化的模型检查了它们的作用:醋酸铅皮下注射到小鼠体内的部位和移植的部位,从供体大鼠获得的主动脉。双膦酸盐对骨吸收和磷酸钙聚集的抑制作用为阿仑膦酸盐>FYB-931>依替膦酸盐和FYB-931>阿仑膦酸盐=依替膦酸盐,分别。在醋酸铅诱导的模型中,FYB-931最有效地抑制了钙化,其次是阿仑膦酸盐和依替膦酸盐。在主动脉移植模型中,只有FYB-931在高剂量时抑制钙化。在这两种模型中,钙化和骨吸收标志物之间没有相关性,抗酒石酸酸性磷酸酶(TRACP)。醋酸铅诱导模型的结果表明,对磷酸钙聚集的抑制作用有助于抑制钙化。两个钙化模型,特别是醋酸铅诱导的模型,由于磷酸钙聚集而不是骨吸收作为其机制,因此可能是对人类钙化反应外推的理想选择。
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.