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.
The family of fibroblast growth factors (FGFs) regulates a plethora of developmental processes, including brain patterning, branching morphogenesis and limb development. Several mitogenic, cytoprotective and angiogenic therapeutic applications of FGFs are already being explored, and the recent discovery of the crucial roles of the endocrine-acting FGF19 subfamily in bile acid, glucose and phosphate homeostasis has sparked renewed interest in the pharmacological potential of this family. This Review discusses traditional applications of recombinant FGFs and small-molecule FGF receptor kinase inhibitors in the treatment of cancer and cardiovascular disease and their emerging potential in the treatment of metabolic syndrome and hypophosphataemic diseases.
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This work was supported by the US National Institutes of Health (NIH) grant R01-DE13686 (to M.M.) and by NIH/NIGMS training grant T32-GM066704-05 (to A.B.).
- Autosomal dominant hypophosphataemic rickets
A hereditary disorder of phosphate wasting characterized by rickets, lower extremity deformities and osteomalacia.
- Lacrimo-auriculo-dento-digital syndrome
(LADD). A syndrome characterized by abnormalities of the digits and teeth, low-set ears and aplasia of the lacrimal and salivary glands. Mutations in FGFR2 and FGF10 are known to cause LADD.
- Kallmann syndrome
This syndrome results from a deficiency of gonadotropin-releasing hormone, which leads to hypogonadism. Mutations in FGFR1c and FGF8 are known to cause Kallmann syndrome.
- Oral mucositis
This condition results from injury to the epithelium of the oral cavity and can vary widely in severity. In the worst cases, oral mucositis can lead to ulceration, infection and the need for assisted feeding.
- Heparan sulphate glycosaminoglycan
(HSGAG). HSGAGs are long chains of repeating disaccharide units that can be variably sulphated or acetylated, allowing for considerable structural diversity. HSGAGs are located in the extracellular matrix at the surface of every cell, where they modulate the activity of a wide range of growth factors and morphogens.
- Exon skipping
A specific type of alternative splicing in which an exon is entirely skipped.
- Alternative splicing
This process increases protein diversity by dividing up the primary RNA gene transcript, excluding certain exons, and then reconnecting the transcript. These alternative ribonucleotide sequences are then translated, giving a variety of protein isoforms.
This condition results from the premature closure of sutures of a developing skull before the completion of brain growth. The brain continues to grow in areas of the skull where sutures have not closed, leading to a malformed cranium.
- Apert's syndrome
One of the most common craniosynostosis syndromes that exhibits severe syndactyly (digit fusion) of the hands and feet. Apert's syndrome is often associated with visceral abnormalities of the cardiovascular, respiratory and urogenital systems.
- Osteoglophonic dysplasia
A bone disorder presenting with dwarfism, vertebral fragility, craniosynostosis and failure to thrive. The term osteoglophonic refers to the 'hollowed out' appearance of the metaphyses in X-rays, which are the growth zones of long bones.
- Pfeiffer's syndrome
A craniosynostosis disorder that can also present with polydactyly.
An aggressive tumour derived from glial cells that exhibits high levels of neovascularization.
- Myeloproliferative syndrome
A progressive disease that can transform into acute leukaemia. Also known as stem cell leukaemia or lymphoma syndrome, it often presents with a T-cell lymphoblastic lymphoma and eosinophilia.
- Crouzon's syndrome
A craniosynostosis syndrome presenting with a beaked nose and bulging, excessively separated eyes (exopthalmos and hypertelorism, respectively).
- Callosal agenesis
An absence of the corpus callosum, the tissue that connects the two hemispheres of the brain.
A condition associated with enlarged lateral ventricles in the brain. Ventriculomegaly can have many causes, one of which is callosal agenesis.
A mild dwarfism syndrome generally presenting with nearly normal cranial and facial characteristics.
- Thanatophoric dysplasia type II
A lethal neonatal skeletal dysplasia associated with a severe cloverleaf-shaped skull deformity.
- Severe achondroplasia with developmental delay and acanthosis nigricans syndrome
This dwarfism syndrome is accompanied by substantial neurological disorders and acanthosis nigricans, which involves a hyperpigmentation of the skin.
- Nitric oxide
Among its many functions, this small molecule relaxes the smooth muscle surrounding blood vessels.
- Brachial plexus
The bundle of nerves located in the axilla (armpit) that descends into the upper limb to provide sensation and motor control.
- Chronic transverse myelitis
Inflammation across the width of one segment of the spinal cord that can lead to destruction of myelin and neurological impairment.
A highly sulphated heparan sulphate glycosaminoglycan (HSGAG). Although it does not act physiologically on FGF–FGFR signalling, it can substitute for other HSGAGs in experimental studies.
These cells form the outer layer of the developing embryo and are responsible for its implantation into the endometrium.
Demineralization of the bones often associated with a lack of vitamin D.
- Secondary hyperparathyroidism
This condition is marked by excessive secretion of parathyroid hormone as a result of low serum calcium levels. It is often seen in patients suffering from kidney disease.
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Beenken, A., Mohammadi, M. The FGF family: biology, pathophysiology and therapy. Nat Rev Drug Discov 8, 235–253 (2009). https://doi.org/10.1038/nrd2792
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Transcriptional regulation of the bovine FGFR1 gene facilitates myoblast proliferation under hypomethylation of the promoter
Journal of Cellular Physiology (2020)
Current Pathobiology Reports (2020)
Inhibition of FGFR2-Signaling Attenuates a Homology-Mediated DNA Repair in GIST and Sensitizes Them to DNA-Topoisomerase II Inhibitors
International Journal of Molecular Sciences (2020)