CYP24 inhibition as a therapeutic target in FGF23-mediated renal phosphate wasting disorders
Xiuying Bai, … , David Goltzman, Andrew C. Karaplis
Xiuying Bai, … , David Goltzman, Andrew C. Karaplis
Published January 19, 2016
Citation Information: J Clin Invest. 2016;126(2):667-680. https://doi.org/10.1172/JCI81928.
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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

Xiuying Bai, Dengshun Miao, Sophia Xiao, Dinghong Qiu, René St-Arnaud, Martin Petkovich, Ajay Gupta, David Goltzman, Andrew C. Karaplis

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Figure 1

Generation of Cyp24–/– Hyp Y mice and bone morphology.

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Generation of Cyp24–/– Hyp Y mice and bone morphology. (A). Southern blo...
(A). Southern blot analysis of tail genomic DNA. The presence of Sry and the absence of Phex were used to identify male mice of the Hyp genotype. (B) Representative contact radiographs of femurs from mice of the 4 indicated genotypes illustrating the increase in bone length observed in Hyp mice following Cyp24 ablation. Arrow shows widening of the growth plate; bracket shows splaying of the epiphysis. (C) μCT of long bones. Top panel: 3D reconstructed front views of the proximal ends of tibiae (arrow illustrates widening and lack of mineralization of the Hyp growth plate); middle panel: longitudinal; bottom panel: cross-sectional views of tibiae obtained from μCT scan images of 52-day-old mice of the indicated genotypes. Quantitative analyses of (D) unmineralized thickness of growth plates, (E) percentage of osteoid volume (OV) per bone volume (BV), and (F) number of osteoclasts per total area, as measured by computer-assisted image analysis. Each value represents the mean ± SEM of determinations in 5 mice of each genotype. *P < 0.05, **P < 0.01, and ***P < 0.001 compared with WT mice; #P < 0.05, ##P < 0.01, and ###P < 0.001 compared with Cyp24–/– mice; and †P < 0.5, ††P < 0.01, and †††P < 0.001 compared with Hyp Y mice, all determined by 1-way ANOVA with Tukey’s multiple comparisons post test.