Increased FGF-23 levels are linked to ineffective erythropoiesis and impaired bone mineralization in myelodysplastic syndromes

Weidner, Heike; Baschant, Ulrike; Lademann, Franziska; Colunga, Maria G. Ledesma; Balaian, Ekaterina; Hofbauer, Christine; Misof, Barbara M.; Roschger, Paul; Blouin, Stéphane; Richards, William G.; Platzbecker, Uwe; Hofbauer, Lorenz C.; Rauner, Martina

doi:10.1172/jci.insight.137062

Cited by 21 publications

(23 citation statements)

References 63 publications

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“…In patients with bone metastasis due to different solid tumors, a higher FGF23 plasma concentration is associated with shorter survival and shorter time to skeletal-related events ( Mansinho et al, 2019 ). Patients with myelodysplastic syndrome (MDS) characterized by impaired hematopoiesis in the bone marrow have a higher FGF23 plasma concentration that is associated with anemia and lower bone mineralization ( Weidner et al, 2020 ). In mice, MDS is paralleled by Fgf23 expression in erythroid precursor cells ( Weidner et al, 2020 ).…”

Section: Fgf23 and Cancermentioning

confidence: 99%

“…Patients with myelodysplastic syndrome (MDS) characterized by impaired hematopoiesis in the bone marrow have a higher FGF23 plasma concentration that is associated with anemia and lower bone mineralization ( Weidner et al, 2020 ). In mice, MDS is paralleled by Fgf23 expression in erythroid precursor cells ( Weidner et al, 2020 ). Multiple myeloma (MM) is characterized by painful bone lesions.…”

Section: Fgf23 and Cancermentioning

confidence: 99%

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Role of Fibroblast Growth Factor 23 (FGF23) and αKlotho in Cancer

Ewendt

Feger

Föller

2021

Front. Cell Dev. Biol.

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Together with fibroblast growth factors (FGFs) 19 and 21, FGF23 is an endocrine member of the family of FGFs. Mainly secreted by bone cells, FGF23 acts as a hormone on the kidney, stimulating phosphate excretion and suppressing formation of 1,25(OH)2D3, active vitamin D. These effects are dependent on transmembrane protein αKlotho, which enhances the binding affinity of FGF23 for FGF receptors (FGFR). Locally produced FGF23 in other tissues including liver or heart exerts further paracrine effects without involvement of αKlotho. Soluble Klotho (sKL) is an endocrine factor that is cleaved off of transmembrane Klotho or generated by alternative splicing and regulates membrane channels, transporters, and intracellular signaling including insulin growth factor 1 (IGF-1) and Wnt pathways, signaling cascades highly relevant for tumor progression. In mice, lack of FGF23 or αKlotho results in derangement of phosphate metabolism and a syndrome of rapid aging with abnormalities affecting most organs and a very short life span. Conversely, overexpression of anti-aging factor αKlotho results in a profound elongation of life span. Accumulating evidence suggests a major role of αKlotho as a tumor suppressor, at least in part by inhibiting IGF-1 and Wnt/β-catenin signaling. Hence, in many malignancies, higher αKlotho expression or activity is associated with a more favorable outcome. Moreover, also FGF23 and phosphate have been revealed to be factors relevant in cancer. FGF23 is particularly significant for those forms of cancer primarily affecting bone (e.g., multiple myeloma) or characterized by bone metastasis. This review summarizes the current knowledge of the significance of FGF23 and αKlotho for tumor cell signaling, biology, and clinically relevant parameters in different forms of cancer.

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Section: Fgf23 and Cancermentioning

confidence: 99%

Section: Fgf23 and Cancermentioning

confidence: 99%

Role of Fibroblast Growth Factor 23 (FGF23) and αKlotho in Cancer

Ewendt

Feger

Föller

2021

Front. Cell Dev. Biol.

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“…FGF-23 is a bone-derived hormone essential for regulating vitamin D and phosphate concentrations [158]. Two forms of FGF-23 have been described: a full-length biologically active protein (iFGF-23) that, upon cleavage, results in a C-terminal inactive fragment (cFGF-23) [159,160]. While iFGF-23 interacts with FGF receptor 1 (FGFR1) to decrease blood phosphate levels in mice, cFGF-23 can directly increase BM erythroid cell numbers in the same manner as treatment with recombinant human (rhEPO) [82].…”

Section: Hif-epo-fgf-23 Axis: Phd2/hif Inhibitionmentioning

confidence: 99%

“…Accordingly, FGF-23 constitutes the link between erythropoiesis and bone homeostasis in both physiological as well as in a variety of pathological conditions [161,162]. Indeed, we recently showed that increased FGF-23 levels are associated with ineffective erythropoiesis and impaired bone mineralization in myelodysplastic syndromes (MDS) [159]. Similarly, in CKD mouse models, the expression of FGF-23 mRNA is significantly increased in bone cells, resulting in reduced bone mineralization [163].…”

Section: Hif-epo-fgf-23 Axis: Phd2/hif Inhibitionmentioning

confidence: 99%

Hypoxia Pathway Proteins are Master Regulators of Erythropoiesis

Watts

Gaete

Rodríguez

et al. 2020

IJMS

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Erythropoiesis is a complex process driving the production of red blood cells. During homeostasis, adult erythropoiesis takes place in the bone marrow and is tightly controlled by erythropoietin (EPO), a central hormone mainly produced in renal EPO-producing cells. The expression of EPO is strictly regulated by local changes in oxygen partial pressure (pO2) as under-deprived oxygen (hypoxia); the transcription factor hypoxia-inducible factor-2 induces EPO. However, erythropoiesis regulation extends beyond the well-established hypoxia-inducible factor (HIF)–EPO axis and involves processes modulated by other hypoxia pathway proteins (HPPs), including proteins involved in iron metabolism. The importance of a number of these factors is evident as their altered expression has been associated with various anemia-related disorders, including chronic kidney disease. Eventually, our emerging understanding of HPPs and their regulatory feedback will be instrumental in developing specific therapies for anemic patients and beyond.

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“…Accordingly, FGF-23 constitutes the link between erythropoiesis and bone homeostasis in both physiological, as well as in a variety of pathological conditions [156,157]. Indeed, we recently showed increased FGF-23 levels associated with ineffective erythropoiesis and impaired bone mineralization in myelodysplastic syndromes (MDS) [158]. Similarly, in CKD mouse models the expression of Fgf23 mRNA is significantly increased in bone cells, resulting in reduced bone mineralization [159].…”

Section: Hif-epo-fgf23 Axis: Phd2/hif Inhibitionmentioning

confidence: 99%

Hypoxia Pathway Proteins are Master Regulators of Erythropoiesis

Watts

Gaete

Rodríguez

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

Erythropoiesis is a complex process driving the production of red blood cells. During homeostasis, adult erythropoiesis takes place in the bone marrow and is tightly controlled by erythropoietin (EPO), a central hormone mainly produced in renal EPO-producing cells. The expression of EPO is strictly regulated by local changes in oxygen partial pressure (pO2) as under deprived oxygen (hypoxia) the transcription factor Hypoxia Inducible Factor-2 induces EPO. However, erythropoiesis regulation extends beyond the well-established HIF-EPO axis, and involves processes modulated by other hypoxia pathway proteins (HPPs), including proteins involved in iron metabolism. The importance of a number of these factors is evident as their altered expression has been associated with various anemia-related disorders, including chronic kidney disease. Eventually, our emerging understanding of HPPs and their regulatory feedback will be instrumental in developing specific therapies for anemic patients and beyond.

show abstract

Increased FGF-23 levels are linked to ineffective erythropoiesis and impaired bone mineralization in myelodysplastic syndromes

Cited by 21 publications

References 63 publications

Role of Fibroblast Growth Factor 23 (FGF23) and αKlotho in Cancer

Role of Fibroblast Growth Factor 23 (FGF23) and αKlotho in Cancer

Hypoxia Pathway Proteins are Master Regulators of Erythropoiesis

Hypoxia Pathway Proteins are Master Regulators of Erythropoiesis

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