title: CYP24 inhibition as a therapeutic target in FGF23-mediated renal phosphate wasting disorders.
abstract: 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 (FGF23R176Q) 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 FGF23R1760-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.
authors.forename: Xiuying
authors.initials: X
authors.lastname: Bai
authors.forename: Dengshun
authors.initials: D
authors.lastname: Miao
authors.forename: Sophia
authors.initials: S
authors.lastname: Xiao
authors.forename: Dinghong
authors.initials: D
authors.lastname: Qiu
authors.forename: René
authors.initials: R
authors.lastname: St-Arnaud
authors.forename: Martin
authors.initials: M
authors.lastname: Petkovich
authors.forename: Ajay
authors.initials: A
authors.lastname: Gupta
authors.forename: David
authors.initials: D
authors.lastname: Goltzman
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Karaplis
mesh_terms: D000818:Animals; D065607:Cytochrome P-450 Enzyme Inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D010710:Phosphates / Q000652:urine*; D051436:Renal Insufficiency, Chronic / Q000188:drug therapy / Q000235:genetics / Q000473:pathology / Q000652:urine; D065668:Vitamin D3 24-Hydroxylase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019282:Wasting Syndrome / Q000188:drug therapy / Q000235:genetics / Q000473:pathology / Q000652:urine
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; C000717427:FGF23 protein, human; C000717428:Fgf23 protein, mouse; D010710:Phosphates; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; C585550:Cyp24a1 protein, mouse; D065668:Vitamin D3 24-Hydroxylase