BoneKEy Reports | BoneKEy Watch

The role of circulating αKlotho in bone metabolism

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DOI:10.1038/bonekey.2013.57

Following up a case history of a patient with a mutation in the gene encoding αKlotho (αKL), a coreceptor for fetal growth factor 23 (FGF23), Smith et al. sought to understand why this mutation produced profound endocrine disturbances, rickets and high levels of FGF23 in the plasma, even though hypophosphatemia was present. Mice were infected with a virus expressing cKL, the proteolytic cleavage product of membrane-bound αKL, to increase their cKL levels.

Treated mice showed dramatic skeletal changes, with reduced bone mineral density and bone mineral content at the distal and midshaft femora. Distal femoral and tibial growth plates were also widened and the bones had reduced radiodensity, leading to spontaneous fractures. Levels of Fgf23 mRNA were over 150 times those in control mice, and the plasma level of Fgf23 was 38–456 times higher. The mice also showed severe hypocalcemia and hypophosphatemia, an effect that was dose dependent.

The mouse model was judged to replicate the original patient, showing the same metabolic bone syndromes associated with enhanced FGF23 production.

Editor’s comment: This study provides experimental evidence that circulating cKL protein can cause hypophosphatemic rickets, and further demonstrates the role of cKL in the regulation of FGF23 levels.

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