Ectopic expression of Klotho in fibroblast growth factor 23 (FGF23)-producing tumors that cause tumor-induced rickets/osteomalacia (TIO)

Yuka Kinoshita,Yuichi Takashi,Nobuaki Ito,Shiro Ikegawa,Hiroyuki Mano,Tetsuo Ushiku,Masashi Fukayama,Masaomi Nangaku,Seiji Fukumoto

doi:10.1016/j.bonr.2018.100192

Abstract

Tumor-induced rickets/osteomalacia (TIO) is a rare paraneoplastic syndrome caused by tumors that ectopically express fibroblast growth factor 23 (FGF23). FGF23 is a bone-derived hormone that regulates serum phosphate concentrations. Patients with TIO develop hypophosphatemic rickets/osteomalacia due to FGF23 excess and suffer from symptoms such as leg deformities, bone pain, skeletal muscle myopathy, and multiple fractures/pseudofractures. Usually, successful surgical removal of the causative tumors normalizes serum FGF23 and phosphate concentrations in patients with TIO. Most FGF23-producing tumors associated with TIO are histologically called phosphaturic mesenchymal tumor, mixed connective tissue variant (PMTMCT). The precise mechanism by which these tumors ectopically overproduce FGF23 outside of bone is yet to be clarified. Therefore, we performed an RNA sequencing analysis of a PMTMCT that was found in the left parotid gland of a patient with TIO. Among the upregulated genes, we focused on Klotho, the protein product of which is a single pass transmembrane protein that works along with an FGF receptor 1c as a receptor complex for FGF23. Subsequent histological analysis confirmed the ectopic expression of Klotho in other PMTMCTs. From these results, we assume that the ectopic expression of Klotho in PTMMCTs enables a positive feedback loop in FGF23 production via the activation of FGF receptor 1c and exacerbates disease manifestations in TIO.

Highlights

Tumor-induced rickets/osteomalacia (TIO) is a rare paraneoplastic syndrome caused by tumors that overproduce fibroblast growth factor 23 (FGF23) (Shimada et al, 2001; Kumar, 2000)
We detected the ectopic expression of Klotho mRNA and Klotho protein in the FGF23-producing tumors that cause TIO
The result of RNA sequencing analysis showed the upregulation of Klotho mRNA in a tumor in a parotid gland compared to the adjacent normal tissue

Summary

Introduction

Tumor-induced rickets/osteomalacia (TIO) is a rare paraneoplastic syndrome caused by tumors that overproduce fibroblast growth factor 23 (FGF23) (Shimada et al, 2001; Kumar, 2000). FGF23 is a bone-derived hormone that regulates serum phosphate concentrations (Fukumoto and Martin, 2009). FGF23 reduces phosphate reabsorption in the proximal renal tubules by downregulating sodium-phosphate cotransporters. FGF23 decreases phosphate absorption in the intestine by reducing serum active vitamin D: 1,25‐dihydroxyvitamin D [1,25(OH)2D] levels (Shimada et al, 2004). Chronic FGF23 excess leads to vitamin D-resistant hypophosphatemia. Adult patients with TIO suffer from symptoms such as bone pain, skeletal muscle myopathy, and multiple fractures/pseudofractures (Minisola et al., 2017). Growth retardation and leg deformities are common features of patients with childhood-onset TIO (Imel et al, 2006)

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Conclusion