Pruning the ricket thicket
Valentin David, Myles Wolf
Valentin David, Myles Wolf
Published January 19, 2016
Citation Information: J Clin Invest. 2016;126(2):473-476. https://doi.org/10.1172/JCI85005.
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Commentary

Pruning the ricket thicket

Abstract

Overexpression of FGF23 results in hypophosphatemic rickets, which is characterized by renal phosphate wasting, inappropriately low circulating levels of the active form of vitamin D, and skeletal abnormalities. The precise mechanisms of how excess FGF23 leads to hypophosphatemic rickets are not clear. In this issue of the JCI, Bai and colleagues demonstrate that deletion or inhibition of CYP24A1, which initiates degradation of the active form of vitamin D, ameliorates skeletal abnormalities in two mouse models of hypophosphatemic rickets. While this work supports an important role for excess CYP24A1 activity in the pathogenesis of FGF23-mediated hypophosphatemic rickets, more work will need to be done before CYP24A1 inhibition can be integrated into the management of patients living with these diseases.

Authors

Valentin David, Myles Wolf

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Figure 1

Vitamin D functions are regulated by a balance of 1,25(OH)2D synthesis and degradation, both systemically and locally, in vitamin D target tissues.

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Vitamin D functions are regulated by a balance of 1,25(OH)2D synthesis a...
(A) In syndromes of FGF23-dependent hypophosphatemic rickets, excess FGF23 production by bone enters the circulation and reduces systemic vitamin D levels through two independent mechanisms in the kidney. FGF23 induces CYP24A1 activity, which converts vitamin D storage [25(OH)D] and active [1,25(OH)2D] forms to inactive metabolites, and it inhibits CYP27B1, which is responsible for converting 25(OH)D to 1,25(OH)2D. These effects of FGF23 are counter-regulated by the opposing effects of PTH. FGF23 also promotes renal phosphate wasting by reducing the expression of sodium-dependent phosphate cotransporters (NPT2) in the kidney and thereby reducing phosphate reabsorption. Hypophosphatemic rickets results as a consequence of these metabolic perturbations, but the primary mediator of the skeletal disease is unclear. (B) Inhibition of Cyp24a1 in murine models of FGF23-dependent hypophosphatemic rickets ameliorates the skeletal defects in these animals. This is thought to result from elevated levels of 1,25(OH)2D locally in the bone, since systemic levels of 1,25(OH)2D, serum phosphate, and calcium are unchanged. These results suggest a pivotal role for FGF23-mediated upregulation of CYP24A1 in the pathogenesis of hypophosphatemic rickets.