Disturbed phosphate homeostasis is a common feature of chronic kidney disease (CKD). High serum levels of FGF-23 are associated with adverse effects on bone metabolism. New findings suggest that inhibition of the vitamin D-inactivating enzyme, CYP24A1, might present a new therapeutic opportunity for the treatment of mineral abnormalities associated with high FGF-23 levels.

FGF-23 regulates mineral metabolism through a series of complex pathways. Its effects on vitamin D are twofold: it inhibits the production of active 1,25[OH]2D by downregulating CYP27B1, the enzyme responsible for 1,25[OH]2D production, while promoting the catabolism of active 1,25[OH]2D by upregulating CYP24A1.

The high levels of CYP24A1 in association with high FGF-23 expression led Andrew Karaplis and his team to investigate whether increased CYP24A1 expression contributes to the pathogenesis of renal phosphate-wasting disorders associated with excess FGF-2 3. The researchers investigated the effects of CYP24A1 deletion in two strains of genetically modified mice with different aetiologies of high FGF-23 expression: Hyp mice — a murine model of X-linked hypophosphataemia — and FGF23R176Q mice, which express a mutant form of FGF-23 described in patients with autosomal dominant hypophosphataemic rickets. Deletion of CYP24A1 by crossing these strains with Cyp24a1−/− mice ameliorated the rachitic bone abnormalities associated with FGF-23 overexpression. This improvement occurred in the absence of improvements in the serum biochemical profile. The researchers also demonstrated that pharmacologic inhibition of CYP24A1 ameliorated the bone abnormalities of Hyp and FGF23R176Q mice. “These findings implicate the extrarenal synthesis of bioactive vitamin D in osteoblasts and chondrocytes, acting in an intracrine and/or autocrine manner in these cells, in the amelioration of bone abnormalities,” says Karaplis. “Moreover, by inhibiting the inactivating enzyme, the amount of active vitamin D required to elicit beneficial effects in patients could potentially be reduced, thereby preventing adverse effects.”