Circulating α-Klotho Levels Are Inversely Correlated to FGF-23 in Tumour Induced Osteomalacia

Tumour induced osteomalacia is characterised by high circulating levels of fibroblast growth factor 23 (FGF23) due to ectopic secretion from mesenchymal tumors. An abundance of FGF23 drives the hypophosphatemia and low 1,25-dihydroxy vitamin D levels characteristic of this condition. The single-pass trans-membrane protein α-klotho is integral for FGF23-mediated receptor activation and its downstream effects. In addition, α-klotho may have a phosphaturic effect independent of FGF-23. The regulation of α-klotho in the face of high circulating FGF23 is currently unknown. We investigated the relationship between circulating FGF23 and α-klotho in patients with TIO. We identified 15 consecutive plasma FGF-23 requests in subjects with confirmed TIO for testing. FGF-23 was measured using Immutopics C-term ELISA kit and soluble α-klotho was measured using the IBL ELISA kit. The group consisted of 7 males and 8 females with an age of 53 ± 20 years (mean ± SD). Only one subject was not on treatment for TIO at the time of sampling. The average circulating levels of FGF23 and α-klotho were 286 ± 244 RU/ml and 644 ± 309 pg/ml respectively. There was an inverse correlation between FGF-23 and α-klotho (Pearson coefficient - 0.28). This inverse correlation may suggest that increasing levels of FGF23 in TIO down-regulate α-klotho expression in the kidney and parathyroid glands leading to reduced circulating levels of α-klotho. Given α-klotho’s role in mediating FGF23 signalling and that α-klotho may be a phosphaturic factor in its own right; such an adaptive mechanism would help partially reduce the renal phosphate wasting seen in TIO. In summary there is an inverse correlation seen between circulating levels of FGF23 and α-klotho in TIO. This may suggest there is a down-regulation of α-klotho expression to limit the phosphate wasting and resultant hypophosphatemia that is seen in TIO.