The FGF family: biology, pathophysiology and therapy

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Abstract
Fibroblast growth factors (FGFs) signal through FGF receptor tyrosine kinases to regulate a wide range of biological processes during development and adulthood. FGF receptors (FGFRs) are involved in the pathogenesis of cancer and skeletal disorders. Experiments in model systems have shown that FGFR-specific inhibitors may be valuable in treating multiple myeloma, bladder and endometrial cancers. FGF1, FGF2 and FGF4 have been studied in clinical trials for the treatment of cardiovascular disease. The results of most of these trials have been unclear. However, some promising prospects remain. In particular, plasmids encoding FGF1 have shown potential in treating peripheral ischaemia. Recombinant FGF7 is Food and Drug Administration approved for the treatment of chemoradiation-induced oral mucositis. Research into the application of FGF7 to treat conditions such as graft-versus-host disease is ongoing. FGF18 increases cartilage formation in rats and may be useful in treating osteoarthritis. The endocrine FGF19 subfamily holds the greatest promise for therapeutic development. These ligands circulate throughout the body owing to weak affinity for HSGAG (heparan sulphate glycosaminoglycan), and they require α-klotho–β-klotho proteins as cofactors for their activity. The α-klotho–β-klotho proteins also determine the target-tissue specificity of FGF19 subfamily ligands. FGF19 negatively regulates bile acid synthesis and recombinant FGF19 increases the metabolic rate of mice. Unfortunately, FGF19 transgenic mice develop hepatocellular carcinomas, and this side effect may impede the pharmaceutical development of FGF19. FGF21 is a mediator of the fasting response that increases glucose uptake, improves insulin sensitivity and reduces serum glucagon and triglyceride levels. In contrast to FGF19, FGF21 is not mitogenic, and FGF21 administration leads to neither oedema nor hypoglycaemia, which are two common side effects of agents that modulate metabolic disorders. FGF21 thus shows great potential for treating type 2 diabetes. FGF23 reduces renal phosphate reabsorption and downregulates vitamin D activation. FGF23 is broadly implicated in human disease, including autosomal-dominant hypophosphataemic rickets, tumour-induced osteomalacia, familial tumoral calcinosis and end-stage kidney disease. Neutralizing antibodies against FGF23 have shown efficacy in model systems and demonstrate the clinical potential of FGF23-specific therapies.