The regulation of FGF23 under physiological and pathophysiological conditions

Rausch, Steffen; Föller, Michael

doi:10.1007/s00424-022-02668-w

Cited by 40 publications

(21 citation statements)

References 121 publications

(150 reference statements)

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“…In terms of nomenclature, FGF19, FGF21 and FGF23 are of often denoted endocrine FGFs (eFGFs), because they are soluble, enter the circulation and can act at a distance (Phan et al, 2021). FGF23 is an eFGF produced in bone that regulates renal phosphate homeostasis, together with vitamin D and parathyroid hormone (PTH) (Neyra et al, 2021;Rausch and Föller, 2022). The membrane-bound and soluble forms of Klotho can both function as coreceptors for FGF23 (Chen G, et al, 2018).…”

Section: Klotho Interactions With Fgf23 and Fgfrsmentioning

confidence: 99%

Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations

Prud’homme

Kurt²,

Wang

2022

Front. Aging

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The α-Klotho protein (henceforth denoted Klotho) has antiaging properties, as first observed in mice homozygous for a hypomorphic Klotho gene (kl/kl). These mice have a shortened lifespan, stunted growth, renal disease, hyperphosphatemia, hypercalcemia, vascular calcification, cardiac hypertrophy, hypertension, pulmonary disease, cognitive impairment, multi-organ atrophy and fibrosis. Overexpression of Klotho has opposite effects, extending lifespan. In humans, Klotho levels decline with age, chronic kidney disease, diabetes, Alzheimer’s disease and other conditions. Low Klotho levels correlate with an increase in the death rate from all causes. Klotho acts either as an obligate coreceptor for fibroblast growth factor 23 (FGF23), or as a soluble pleiotropic endocrine hormone (s-Klotho). It is mainly produced in the kidneys, but also in the brain, pancreas and other tissues. On renal tubular-cell membranes, it associates with FGF receptors to bind FGF23. Produced in bones, FGF23 regulates renal excretion of phosphate (phosphaturic effect) and vitamin D metabolism. Lack of Klotho or FGF23 results in hyperphosphatemia and hypervitaminosis D. With age, human renal function often deteriorates, lowering Klotho levels. This appears to promote age-related pathology. Remarkably, Klotho inhibits four pathways that have been linked to aging in various ways: Transforming growth factor β (TGF-β), insulin-like growth factor 1 (IGF-1), Wnt and NF-κB. These can induce cellular senescence, apoptosis, inflammation, immune dysfunction, fibrosis and neoplasia. Furthermore, Klotho increases cell-protective antioxidant enzymes through Nrf2 and FoxO. In accord, preclinical Klotho therapy ameliorated renal, cardiovascular, diabetes-related and neurodegenerative diseases, as well as cancer. s-Klotho protein injection was effective, but requires further investigation. Several drugs enhance circulating Klotho levels, and some cross the blood-brain barrier to potentially act in the brain. In clinical trials, increased Klotho was noted with renin-angiotensin system inhibitors (losartan, valsartan), a statin (fluvastatin), mTOR inhibitors (rapamycin, everolimus), vitamin D and pentoxifylline. In preclinical work, antidiabetic drugs (metformin, GLP-1-based, GABA, PPAR-γ agonists) also enhanced Klotho. Several traditional medicines and/or nutraceuticals increased Klotho in rodents, including astaxanthin, curcumin, ginseng, ligustilide and resveratrol. Notably, exercise and sport activity increased Klotho. This review addresses molecular, physiological and therapeutic aspects of Klotho.

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Section: Klotho Interactions With Fgf23 and Fgfrsmentioning

confidence: 99%

Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations

Prud’homme

Kurt²,

Wang

2022

Front. Aging

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“…In addition to the local regulators described above, various systemic factors also regulate FGF23 levels and include 1,25(OH) 2 D, PTH, Pi, iron, hypoxia, inflammation, insulin, estrogen, and the circadian rhythm [68,[114][115][116][117][118][119][120][121]. Therefore, the regulation of FGF23 is complex and multifactorial and has not yet been elucidated in detail.…”

Section: Systemic Regulators Of Fgf23mentioning

confidence: 99%

“…This review describes some of the systemic regulators. There are already several excellent reviews on the regulators of FGF23 [114,119].…”

Section: Systemic Regulators Of Fgf23mentioning

confidence: 99%

Advances in understanding of phosphate homeostasis and related disorders

Michigami

2022

Endocr J

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Inorganic phosphate (Pi) in the mammalian body is balanced by its influx and efflux through the intestines, kidneys, bones, and soft tissues, at which several sodium/Pi co-transporters mediate its active transport. Pi homeostasis is achieved through the complex counter-regulatory feedback balance between fibroblast growth factor 23 (FGF23), 1,25-dihydroxyvitamin D (1,25(OH) 2 D), and parathyroid hormone. FGF23, which is mainly produced by osteocytes in bone, plays a central role in Pi homeostasis and exerts its effects by binding to the FGF receptor (FGFR) and αKlotho in distant target organs. In the kidneys, the main target, FGF23 promotes the excretion of Pi and suppresses the production of 1,25(OH) 2 D. Deficient and excess FGF23 result in hyperphosphatemia and hypophosphatemia, respectively. FGF23-related hypophosphatemic rickets/osteomalacia include tumor-induced osteomalacia and various genetic diseases, such as X-linked hypophosphatemic rickets. Coverage by the national health insurance system in Japan for the measurement of FGF23 and the approval of burosumab, an FGF23-neutralizing antibody, have had a significant impact on the diagnosis and treatment of FGF23-related hypophosphatemic rickets/osteomalacia. Some of the molecules responsible for genetic hypophosphatemic rickets/osteomalacia are highly expressed in osteocytes and function as local regulators of FGF23 production. A number of systemic factors also regulate FGF23 levels. Although the mechanisms responsible for Pi sensing in mammals have not yet been elucidated in detail, recent studies have suggested the involvement of FGFR1. The further clarification of the mechanisms by which osteocytes detect Pi levels and regulate FGF23 production will lead to the development of better strategies to treat hyperphosphatemic and hypophosphatemic conditions.

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“…Increased serum levels of intact FGF23 may be observed in patients with inflammatory diseases (57), and various proinflammatory cytokines, such as tumor necrosis factor a, IL-1b, and IL-6, have been reported to increase the expression of Fgf23 (58). Several mechanisms, including the activation of the HIF pathway, the involvement of NF-kB and signal transducer and activator of transcription 3, and lipocalin 2-mediated induction, have been suggested to contribute to inflammationassociated increases in the production of FGF23 (59)(60)(61)(62).…”

Section: Systemic Regulators Of Fgf23 Production In Osteocytesmentioning

confidence: 99%

“…Many other factors have also been suggested to regulate the production of FGF23, and there are several excellent review articles on this topic (57,58). Therefore, the regulation of FGF23 is multifactorial and complex, and has not yet been elucidated in detail.…”

Section: Systemic Regulators Of Fgf23 Production In Osteocytesmentioning

confidence: 99%

Roles of osteocytes in phosphate metabolism

Michigami

2022

Front. Endocrinol.

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Osteocytes are dendritic cells in the mineralized bone matrix that descend from osteoblasts. They play critical roles in controlling bone mass through the production of sclerostin, an inhibitor of bone formation, and receptor activator of nuclear factor κ B ligand, an inducer of osteoblastic bone resorption. Osteocytes also govern phosphate homeostasis through the production of fibroblast growth factor 23 (FGF23), which lowers serum phosphate levels by increasing renal phosphate excretion and reducing the synthesis of 1,25-dihydroxyvitamin D (1,25(OH)2D), an active metabolite of vitamin D. The production of FGF23 in osteocytes is regulated by various local and systemic factors. Phosphate-regulating gene homologous to endopeptidase on X chromosome (PHEX), dentin matrix protein 1 (DMP1), and family with sequence similarity 20, member C function as local negative regulators of FGF23 production in osteocytes, and their inactivation causes the overproduction of FGF23 and hypophosphatemia. Sclerostin has been suggested to regulate the production of FGF23, which may link the two functions of osteocytes, namely, the control of bone mass and regulation of phosphate homeostasis. Systemic regulators of FGF23 production include 1,25(OH)2D, phosphate, parathyroid hormone, insulin, iron, and inflammation. Therefore, the regulation of FGF23 in osteocytes is complex and multifactorial. Recent mouse studies have suggested that decreases in serum phosphate levels from youth to adulthood are caused by growth-related increases in FGF23 production by osteocytes, which are associated with the down-regulation of Phex and Dmp1.

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The regulation of FGF23 under physiological and pathophysiological conditions

Cited by 40 publications

References 121 publications

Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations

Pathobiology of the Klotho Antiaging Protein and Therapeutic Considerations

Advances in understanding of phosphate homeostasis and related disorders

Roles of osteocytes in phosphate metabolism

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