Targeting Fibroblast Growth Factor 23 Signaling with Antibodies and Inhibitors, Is There a Rationale?

Seiji Fukumoto

doi:10.3389/fendo.2018.00048

Abstract

Fibroblast growth factor 23 (FGF23) is a phosphotropic hormone mainly produced by bone. FGF23 reduces serum phosphate by suppressing intestinal phosphate absorption through reducing 1,25-dihydroxyvitamin D and proximal tubular phosphate reabsorption. Excessive actions of FG23 result in several kinds of hypophosphatemic rickets/osteomalacia including X-linked hypophosphatemic rickets (XLH) and tumor-induced osteomalacia. While neutral phosphate and active vitamin D are standard therapies for child patients with XLH, these medications have several limitations both in their effects and adverse events. Several approaches that inhibit FGF23 actions including anti-FGF23 antibodies and inhibitors of FGF signaling have been shown to improve phenotypes of model mice for FG23-related hypophosphatemic diseases. In addition, clinical trials indicated that a humanized anti-FGF23 antibody increased serum phosphate and improved quality of life in patients with XLH. Furthermore, circulatory FGF23 is high in patients with chronic kidney disease (CKD). Many epidemiological studies indicated the association between high FGF23 levels and various adverse events especially in patients with CKD. However, it is not known whether the inhibition of FGF23 activities in patients with CKD is beneficial for these patients. In this review, recent findings concerning the modulation of FGF23 activities are discussed.

Highlights

Fibroblast growth factor 23 (FGF23) was identified as a responsible gene for autosomal dominant hypophosphatemic rickets (ADHR) in 2000 by positional cloning [1]
PHEX, phosphate-regulating gene with homologies to endopeptidases on the X chromosome; FGF23, fibroblast growth factor 23; DMP1, dentin matrix protein 1; ENPP1, ectonucleotide pyrophosphatase/phosphodiesterase 1; FGFR1, fibroblast growth factor receptor 1; PTH1R, parathyroid hormone 1 receptor; FAM20C, family with sequence similarity 20, member C; GNAS1, guanine nucleotide binding protein, alpha-stimulating activity polypeptide 1; HRAS, Harvey rat sarcoma viral oncogene homolog; KRAS, Kirsten rat sarcoma rival oncogene homolog: NRAS, neuroblastoma RAS viral oncogene homolog; FN, fibronectin; FGFR, FGF receptor
Repeated administration of these antibodies enhanced longitudinal growth of long bones, increased bone mineral density and corrected impaired mineralization of Hyp mice [39]. These antibodies increased grip power and spontaneous movement of Hyp mice [40]. These results suggested that the inhibition of FGF23 activities by FGF23 antibodies can ameliorate biochemical, morphological, histological and clinical abnormalities of patients with FGF23-related hypophosphatemic rickets/osteomalacia

Summary

Seiji Fukumoto*

While neutral phosphate and active vitamin D are standard therapies for child patients with XLH, these medications have several limitations both in their effects and adverse events. Several approaches that inhibit FGF23 actions including anti-FGF23 antibodies and inhibitors of FGF signaling have been shown to improve phenotypes of model mice for FG23-related hypophosphatemic diseases. Clinical trials indicated that a humanized anti-FGF23 antibody increased serum phosphate and improved quality of life in patients with XLH. Many epidemiological studies indicated the association between high FGF23 levels and various adverse events especially in patients with CKD. It is not known whether the inhibition of FGF23 activities in patients with CKD is beneficial for these patients.

INTRODUCTION

Biliary atresia

Targeting FGF Receptor

Targeting of Downstream Signals from FGF Receptor

CONCLUSION