The Klotho proteins in health and disease

Abstract

The Klotho proteins, αKlotho and βKlotho, are essential components of endocrine fibroblast growth factor (FGF) receptor complexes, as they are required for the high-affinity binding of FGF19, FGF21 and FGF23 to their cognate FGF receptors (FGFRs). Collectively, these proteins form a unique endocrine system that governs multiple metabolic processes in mammals. FGF19 is a satiety hormone that is secreted from the intestine on ingestion of food and binds the βKlotho–FGFR4 complex in hepatocytes to promote metabolic responses to feeding. By contrast, under fasting conditions, the liver secretes the starvation hormone FGF21, which induces metabolic responses to fasting and stress responses through the activation of the hypothalamus–pituitary–adrenal axis and the sympathetic nervous system following binding to the βKlotho–FGFR1c complex in adipocytes and the suprachiasmatic nucleus, respectively. Finally, FGF23 is secreted by osteocytes in response to phosphate intake and binds to αKlotho–FGFR complexes, which are expressed most abundantly in renal tubules, to regulate mineral metabolism. Growing evidence suggests that the FGF–Klotho endocrine system also has a crucial role in the pathophysiology of ageing-related disorders, including diabetes, cancer, arteriosclerosis and chronic kidney disease. Therefore, targeting the FGF–Klotho endocrine axes might have therapeutic benefit in multiple systems; investigation of the crystal structures of FGF–Klotho–FGFR complexes is paving the way for the development of drugs that can regulate these axes.

Key points

  • The Klotho proteins αKlotho and βKlotho are essential components of endocrine fibroblast growth factor (FGF) receptor complexes, as they are required for the high-affinity binding of FGF19, FGF21 and FGF23 to their cognate FGF receptors.

  • FGF21 is a starvation hormone that induces stress responses by activating the sympathetic nervous system and the hypothalamus–pituitary–adrenal axis.

  • FGF19 is a satiety hormone that promotes metabolic responses to feeding.

  • FGF23 is a phosphaturic hormone; increased FGF23 levels in patients with early-stage chronic kidney disease or elderly individuals is indicative of excess phosphate intake relative to the residual nephron number.

  • Calciprotein particles are colloids of calcium phosphate adsorbed to fetuin A, which increase in concentration as renal function declines and that can induce innate immune responses and cell death, suggesting that they are mediators of phosphate-induced damage.

  • Solving the crystal structure of αKlotho and βKlotho will facilitate the development of agonists and antagonists of endocrine FGFs, which will be potentially useful for the treatment of various disorders, including chronic kidney disease and other ageing-related disorders.

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Fig. 1: Structural basis of FGF23–αKlotho–FGFR1c complex formation.
Fig. 2: The FGF23–αKlotho endocrine axis.
Fig. 3: Pathophysiology of CKD progression.
Fig. 4: CPP-mediated inflammation and vascular damage.
Fig. 5: Membrane αKlotho and soluble αKlotho.
Fig. 6: The FGF21–βKlotho endocrine axis.
Fig. 7: The FGF15/FGF19–βKlotho endocrine axis.

Notes

  1. 1.

    Ccr, creatinine clearance; Pcr, serum creatinine concentration; Pp, serum phosphate concentration; Ucr, urinary creatinine concentration; Up, urinary phosphate concentration; V, 24-hour urinary volume.

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Acknowledgements

The author’s work is supported by the Japan Agency for Medical Research and Development (AMED) Core Research for Evolutionary Medical Science and Technology (CREST), AMED (JP18gm0610012) and ACT-MS (18im0210806h0001), the Japan Society for the Promotion of Science (16H05302, 16K15470) and the Japan Aerospace Exploration Agency (JAXA).

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Glossary

Hereditary phosphate-wasting syndromes

Inherited disorders in which the disease symptoms are related to the depletion of phosphorus in the body owing to increased urinary phosphate excretion and resulting in hypophosphataemia and disrupted bone mineralization.

Inappropriately normal

Normal protein serum levels when they should be outside of the normal range owing to concurrent levels of other serum proteins. This effect is indicative of impaired physiological responses.

Rickets

A condition characterized by impaired (low) bone mineralization that results in weak, soft bones with increased osteoid (unmineralized bone matrix) in children. In adults, this condition is termed osteomalacia.

Breakpoint

Location in a chromosome where a genomic DNA sequence has been disrupted by deletion, translocation or insertion.

CKD–MBD

Denotes chronic kidney disease (CKD) complications that are associated with and are likely caused by disturbed calcium and phosphate metabolism and by abnormal serum levels of fibroblast growth factor 23 (FGF23), vitamin D, and parathyroid hormone. The term CDK–mineral and bone disorder (CKD–MBD) is used to describe cardiovascular and bone disorders in CKD, including vascular calcification, cardiac hypertrophy and renal osteodystrophy.

Postprandial

The period that follows the ingestion of food.

Sarcopenia

The degenerative decline in skeletal muscle volume and strength with ageing.

Osteopenia

A condition of low bone mineral density. Osteoporosis is a clinical diagnosis of osteopenia that is associated with a decrease in both bone matrix and bone mineral density, as well as altered bone microarchitecture.

Emphysematous lung

Lung tissue that is affected by pulmonary emphysema, which is characterized by enlarged alveolar spaces and damaged alveolar walls.

Colloids

Uniform mixtures of small particles (dispersoids) in the dispersion medium. Dispersoids are not dissolved but are evenly distributed in the dispersion medium.

Arteriosclerosis

A condition that includes two distinct pathologies, atherosclerosis and vascular calcification. Atherosclerosis is characterized by the accumulation of foam cells (macrophages laden with lipids) in the tunica intima, potentially causing obstruction of blood flow. By contrast, vascular calcification occurs in the tunica media and minimally obstructs the blood flow but increases vascular stiffness.

Flow-mediated dilatation

Clinical test in which the expansion rate of the brachial artery is calculated to evaluate vascular endothelial function.

Torpor

Short-term hibernation-like state that is associated with a low body temperature and inactivity.

Suprachiasmatic nucleus

(SCN). Cluster of neurons in the hypothalamus that function as the master circadian pacemaker. Some of these neurons have a direct projection to corticotropin-releasing factor-producing neurons in the paraventricular nucleus.

Nucleus of the solitary tract

(NTS). Cluster of sensory neurons in the medulla oblongata that are innervated from some cranial nerves, including vagus nerves, and project to various nuclei in the brainstem and parasympathetic neurons. It is also known as the central relay for the baroreflex that maintains blood pressure.

Progeroid syndrome

Hereditary disorder in which there are multiple signs and symptoms of ageing in individuals in the early stages of life. Examples include Werner syndrome, Hutchinson–Gilford syndrome, xeroderma pigmentosum and Cockayne syndrome. Patients with progeroid syndromes have defects in DNA repair systems.

Bile acid pool

Amount of bile acids held in the intestine, portal circulation, liver and gall bladder. Bile acids secreted into the intestine are mostly reabsorbed and returned to the liver to be secreted into the intestine again (enterohepatic circulation). The liver synthesizes the same amount of bile acids that are lost in the faeces to maintain the bile acid pool size.

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Kuro-o, M. The Klotho proteins in health and disease. Nat Rev Nephrol 15, 27–44 (2019). https://doi.org/10.1038/s41581-018-0078-3

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