Abstract
Bai X, Miao D, Xiao S, et al.
J Clin Invest 2016 Jan 19. DOI: 10.1172/JCI81928.
Fibroblast growth factor-23 (FGF23) is an osteocyte-derived circulating protein with multiple actions that promote renal phosphate excretion. Accordingly, excess FGF23 activity underpins a number of renal phosphate handling disorders characterised by severe bone loss, including inherited forms of hypophosphataemic rickets and tumour-induced osteomalacia.
FGF23 acts partly by upregulation of vitamin D 24-hydroxylase (CYP24), which inactivates 1,25 vitamin D by 24-hydroxylation. In this preclinical study, the authors generated strains of genetically modified mice which lack CYP24 in combination with two other mutations corresponding to the X-linked and autosomal dominant forms of hypophosphataemic rickets. These disorders are characterised by excess FGF23 due to reduced degradation. They then corroborated their findings using a pharmacological inhibitor of CYP24.
The key finding from this study was that both genetic and pharmacological ablation of CYP24 led to substantial improvement in the bone phenotype associated with FGF23 overactivity. Interestingly, the serum biochemistry did not improve in either model, the possible reasons for which are discussed in the article. The authors propose CYP24 inhibition as a potential future treatment for renal phosphate wasting disorders.