CYP24 inhibition as a therapeutic target in FGF23-mediated renal phosphate wasting disorders
CYP24 inhibition as a therapeutic target in FGF23-mediated renal phosphate wasting disorders
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DOI：
10.1172/jci81928
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发表时间：
2016-02-01
影响因子：
15.9
通讯作者：
Karaplis, Andrew C.
中科院分区：
文献类型：
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作者：
Bai, Xiuying;Miao, Dengshun;Karaplis, Andrew C.
CYP 24 A1（以下简称为CYP 24）酶活性在维生素D代谢物的失活中起关键作用。基础肾和肾外CYP 24通常较低，但其底物1，25-二羟维生素D高度诱导。不平衡的高和/或持久的CYP 24表达已被认为是慢性肾病、癌症和银屑病等疾病的基础，否则这些疾病对补充维生素D有良好的反应。使用转基因小鼠，我们已经表明，高水平的成纤维细胞生长因子23（FGF 23）引起的肾磷酸盐消耗性低磷酸盐血症状态也与肾脏Cyp 24表达增加有关，表明升高的CYP 24活性是这些疾病的病理生理学的关键。因此，我们将2种小鼠品系杂交到Cyp 24空白背景上，每种小鼠品系具有高水平循环FGF 23的不同病因。具体来说，我们评估了Cyp 24缺乏症Hyp小鼠，小鼠同源的X-连锁显性低磷血症佝偻病，和转基因小鼠过度表达突变型FGF 23（FGF 23（R1760）），这是与常染色体显性形式的低磷血症佝偻病。在这些人类疾病的鼠模型中Cyp 24的缺失导致佝偻病/骨软化骨异常在血清生化谱没有任何改善的情况下几乎完全恢复。此外，用CYP 24抑制剂CTA 102治疗Hyp和FGF 23（R1760）转基因小鼠也改善了他们的佝偻病骨。我们的研究结果将CYP 24活性与FGF 23依赖性肾磷酸盐消耗状态的病理生理学联系起来，并暗示药物CYP 24抑制可作为其治疗的辅助治疗。
CYP24A1 (hereafter referred to as CYP24) enzymatic activity is pivotal in the inactivation of vitamin D metabolites. Basal renal and extrarenal CYP24 is usually low but is highly induced by its substrate 1,25-dihydroxyvitamin D. Unbalanced high and/or long-lasting CYP24 expression has been proposed to underlie diseases like chronic kidney disease, cancers, and psoriasis that otherwise should favorably respond to supplemental vitamin D. Using genetically modified mice, we have shown that renal phosphate wasting hypophosphatemic states arising from high levels of fibroblast growth factor 23 (FGF23) are also associated with increased renal Cyp24 expression, suggesting that elevated CYP24 activity is pivotal to the pathophysiology of these disorders. We therefore crossed 2 mouse strains, each with distinct etiology for high levels of circulating FGF23, onto a Cyp24-null background. Specifically, we evaluated Cyp24 deficiency in Hyp mice, the murine homolog of X-linked dominant hypophosphatemic rickets, and transgenic mice that overexpress a mutant FGF23 (FGF23(R1760)) that is associated with the autosomal dominant form of hypophosphatemic rickets. Loss of Cyp24 in these murine models of human disease resulted in near-complete recovery of rachitic/osteomalacic bony abnormalities in the absence of any improvement in the serum biochemical profile. Moreover, treatment of Hyp and FGF23(R1760)-transgenic mice with the CYP24 inhibitor CTA102 also ameliorated their rachitic bones. Our results link CYP24 activity to the pathophysiology of FGF23-dependent renal phosphate wasting states and implicate pharmacologic CYP24 inhibition as a therapeutic adjunct for their treatment.