Research Article: Antibody-Mediated Activation of FGFR1 Induces FGF23 Production and Hypophosphatemia

Date Published: February 22, 2013

Publisher: Public Library of Science

Author(s): Ai-Luen Wu, Bo Feng, Mark Z. Chen, Ganesh Kolumam, Jose Zavala-Solorio, Shelby K. Wyatt, Vineela D. Gandham, Richard A. D. Carano, Junichiro Sonoda, Makoto Makishima. http://doi.org/10.1371/journal.pone.0057322

Abstract

The phosphaturic hormone Fibroblast Growth Factor 23 (FGF23) controls phosphate homeostasis by regulating renal expression of sodium-dependent phosphate co-transporters and cytochrome P450 enzymes involved in vitamin D catabolism. Multiple FGF Receptors (FGFRs) can act as receptors for FGF23 when bound by the co-receptor Klotho expressed in the renal tubular epithelium. FGFRs also regulate skeletal FGF23 secretion; ectopic FGFR activation is implicated in genetic conditions associated with FGF23 overproduction and hypophosphatemia. The identity of FGFRs that mediate the activity of FGF23 or that regulate skeletal FGF23 secretion remains ill defined. Here we report that pharmacological activation of FGFR1 with monoclonal anti-FGFR1 antibodies (R1MAb) in adult mice is sufficient to cause an elevation in serum FGF23 and mild hypophosphatemia. In cultured rat calvariae osteoblasts, R1MAb induces FGF23 mRNA expression and FGF23 protein secretion into the culture medium. In a cultured kidney epithelial cell line, R1MAb acts as a functional FGF23 mimetic and activates the FGF23 program. siRNA-mediated Fgfr1 knockdown induced the opposite effects. Taken together, our work reveals the central role of FGFR1 in the regulation of FGF23 production and signal transduction, and has implications in the pathogenesis of FGF23-related hypophosphatemic disorders.

Partial Text

Inorganic phosphate (phosphorus) plays a crucial role in many biological processes including bone mineralization, vascular function, and cellular activity; therefore, its level in the body must be tightly regulated. Fibroblast Growth Factor 23 (FGF23) is an endocrine member of the FGF superfamily produced by osteocytes in the bone [1]–[3]. It acts as an important determinant of phosphate homeostasis by controlling renal phosphate transport as well as vitamin D catabolism. These activities are mediated, at least in part, by transcriptional regulation of genes encoding Na-dependent phosphate co-transporters, NPT2a and NPT2c, as well as cytochrome P450 enzymes, CYP24a1 and CYP27b1, that are respectively involved in the production and the catabolism of active vitamin D (1, 25(OH)2D3, calcitriol) in the kidney [4]–[6]. Genetic disorders with altered circulating levels of phosphate are often associated with dysregulation of the FGF23 pathway. For example, overproduction of FGF23 in osteoblastomas or stabilizing mutations in FGF23 protein is sufficient to cause hypophosphatemia, leading to osteomalacia or hypophosphatemic rickets in humans [5], [7]. In addition, inactivating mutations in genes such as dentin matrix acidic phosphoprotein 1 (Dmp1) [8], Phosphate regulating endopeptidase homolog, X-linked (Phex) [9], or Ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1) [10], [11], have been shown to increase skeletal secretion of FGF23, resulting in hypophosphatemic rickets.

A number of previous studies have implicated FGF23 and FGFRs in the regulation of phosphate metabolism; however, the identity of FGFR isoforms that are functionally important in phosphate regulation remains elusive. In the current study, we used selective antibody activators of FGFR1 to study the effects of systemic FGFR1 activation on phosphate homeostasis. Our results demonstrate that activation of FGFR1, but not other FGFRs, is sufficient to induce FGF23 expression and the resulting hypophosphatemia in adult mice. In addition, FGFR1 activation in cultured kidney epithelial cells is sufficient to induce FGF23 program. siRNA-mediated Fgfr1 knockdown induced the opposite effects. These results complement previous genetic studies with mice deficient for each FGFR isoform, and suggest the central role of FGFR1 in the FGF23 signaling network (Fig. 8).

Source:

http://doi.org/10.1371/journal.pone.0057322

 

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