Strategies to lower fibroblast growth factor 23 bioactivity

Abstract

Fibroblast growth factor 23 (FGF23) is a circulating hormone derived from the bone whose release is controlled by many factors and exerts a multitude of systemic actions. There are congenital and acquired disorders of increased and decreased FGF23 levels. In chronic kidney disease (CKD), elevations of FGF23 levels can be 1000-fold above the upper physiological limit. It is still debated whether this high FGF23 in CKD is a biomarker or causally related to morbidity and mortality. Data from human association studies support pathogenicity, while experimental data are less robust. Knowledge of the biology and pathobiology of FGF23 has generated a plethora of means to reduce FGF23 bioactivity at many levels that will be useful for therapeutic translations. This article summarizes these approaches and addresses several critical questions that still need to be answered.

Keywords: CKD; FGF23; Klotho; chronic renal failure; mineral metabolism.

FIGURE 1

Production and action of endocrine FGF23 and strategies to lower FGF23 bioactivity. 1. Reduce production. Achieved by reduction of P intake and absorption (see Figure 2) and pharmacologically by calcimimetics. 2. Inhibit glycosylation of newly synthesized FGF23 by small molecules. Glycosylation of FGF23 by GALNT3 (UDP-N-acetyl-alpha-D-galactosamine: polypeptide N-acetylgalactosaminyltransferase 3) protects FGF23 from cleavage by furin proprotein convertase (PPC). Inhibition of GALNT3 results in accelerated FGF23 cleavage and clearance. 3. Neutralizing antibodies to circulating FGF23 reduce circulating active FGF23 4. Exogenous C-term fragment of FGF23 competitively blocks full-length FGF23 on-target action on the FGFR1–Klotho coreceptors (see Figure 3). 5. FGFR4 inhibitors block the off-target effects of FGF23 on FGFR4. 6. Pan-FGFR inhibitors block FGFR1–Klotho coreceptor complex and the other FGFRs.

FIGURE 2

Lowering FGF23 by decreasing P load. P is ingested as organic or inorganic (additive to natural diet) forms. P is released by luminal phosphatases and absorbed via paracellular and transcellular routes. 1. Dietary restriction of total P intake or P modification, switching from high to low bioavailable P (from inorganic to organic P). 2. Luminal P binders can be divalent metal (Ca²⁺, Mg²⁺ and Fe²⁺), trivalent metal (Al³⁺ and La³⁺) and anion exchange polymers. 3. Inhibition of transcellular transport by direct or indirect inhibition of NaPi-2b. 4. Blocking paracellular transport is achieved by lumen-restricted inhibition of apical NHE3 with secondary effects on paracellular permeability.

FIGURE 3

Structural basis of the antagonistic action of FGF23 C-terminus. FGF23 is naturally cleaved by the furin PPC (left). FGF23 engages the FGFR1–Klotho coreceptor complex and activates signalling. The natural C-terminal tail of FGF23 (C-term) or shorter minimal binding regions of the C-term binds to the Kl1 and Kl2 domains on Klotho but not FGFR1 and does not activate FGF23 signalling and bioactivity. Molar excess of C-term functions as a specific blocker of FGF23 action on FGFR1–Klotho. Images derived from Chen et al. [42].