PAI-1 is a critical regulator of FGF23 homeostasis

Eren, Mesut; Place, Aaron T.; Thomas, Paul M.; Flevaris, Panagiotis; Miyata, Toshio; Vaughan, Douglas E.

doi:10.1126/sciadv.1603259

Cited by 27 publications

(25 citation statements)

References 52 publications

(77 reference statements)

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“…PAI‐1 may enhance FGF23 levels by inhibiting furin‐like proteases . In line with this, plasminogen activators (PAs) directly cleave FGF23 .…”

Section: Homeostatic Regulation Of Fgf23mentioning

confidence: 84%

“…Impaired renal function in CKD or acute kidney injury (AKI) is a major stimulus of FGF23 production . In animal models of AKI, FGF23 rises within hours and before onset of hyperphosphataemia .…”

Section: Fgf23 Regulation: Insights From Rare Disorders and Renal Dismentioning

confidence: 99%

“…Adipokines, adipose tissue‐derived hormones, like leptin and plasminogen activator inhibitor‐1 (PAI‐1) are positive regulators of FGF23. PAI‐1 may enhance FGF23 levels by inhibiting furin‐like proteases .…”

Section: Homeostatic Regulation Of Fgf23mentioning

confidence: 99%

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Regulation of fibroblast growth factor 23 (FGF23) in health and disease

et al. 2019

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Fibroblast growth factor 23 (FGF23) is mainly produced in the bone and, upon secretion, forms a complex with a FGF receptor and coreceptor αKlotho. FGF23 can exert several endocrine functions, such as inhibiting renal phosphate reabsorption and 1,25‐dihydroxyvitamin D3 production. Moreover, it has paracrine activities on several cell types, including neutrophils and hepatocytes. Klotho and Fgf23 deficiencies result in pathologies otherwise encountered in age‐associated diseases, mainly as a result of hyperphosphataemia‐dependent calcification. FGF23 levels are also perturbed in the plasma of patients with several disorders, including kidney or cardiovascular diseases. Here, we review mechanisms controlling FGF23 production and discuss how FGF23 regulation is perturbed in disease.

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“…PAI‐1 may enhance FGF23 levels by inhibiting furin‐like proteases . In line with this, plasminogen activators (PAs) directly cleave FGF23 .…”

Section: Homeostatic Regulation Of Fgf23mentioning

confidence: 84%

Section: Fgf23 Regulation: Insights From Rare Disorders and Renal Dismentioning

confidence: 99%

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Regulation of fibroblast growth factor 23 (FGF23) in health and disease

et al. 2019

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“…and a series of analogues with improved pharmacological and toxicological properties, including TM5509 and TM5614 44,45 . A number of preclinical studies have demonstrated that this series of compounds is capable of affecting a number of metabolic, fibrotic, aging-related disorders, and hematopoietic regeneration [46][47][48][49][50] . In this study, we provide the first evidence that inhibition of iPAI-1 can be of therapeutic benefit in the treatment of leukemia.…”

Section: Discussionmentioning

confidence: 99%

Targeting of plasminogen activator inhibitor-1 activity promotes elimination of chronic myeloid leukemia stem cells

Yahata¹,

Ibrahim²,

Hirano³

et al. 2020

haematol

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Targeting of plasminogen activator inhibitor-1 activity promotes elimination of chronic myeloid leukemia stem cells. Word counts: The submission includes 3,997 words in the main text; 192 words in the abstract; 6 figures; 2 supplemental figures; 1 supplemental table; 1 supplemental method; 50 references. 2 AbstractTherapeutic strategies that target leukemic stem cells (LSCs) provide potential advantages in the treatment of chronic myeloid leukemia (CML). Here, we show that selective blockade of plasminogen activator inhibitor-1 (PAI-1) enhances the susceptibility of CML-LSCs to tyrosine kinase inhibitor (TKI), which facilitates the eradication of CML-LSCs and leads to sustained remission of the disease. We demonstrated for the first time that TGF-β−PAI-1 axis was selectively augmented in CML-LSCs in the bone marrow (BM), whereby protecting CML-LSCs from TKI treatment. Furthermore, the combined administration of TKI plus a PAI-1 inhibitor, in a mouse model of CML, significantly enhanced the eradication of CML cells in the BM and prolonged the survival of CML mice. The combined therapy of imatinib and a PAI-1 inhibitor prevented the recurrence of CML-like disease in serially transplanted recipients, indicating the elimination of CML-LSCs. Interestingly, PAI-1 inhibitor treatment augmented membrane-type matrix metalloprotease-1 (MT1-MMP)-dependent motility of CML-LSCs, and the anti-CML effect of PAI-1 inhibitor was extinguished by the neutralizing antibody for MT1-MMP, underlining the mechanistic importance of MT1-MMP. Our findings provide evidence of, and a rationale for, a novel therapeutic tactic, based on the blockade of PAI-1 activity, for CML patients.

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“…The C-terminal domain is essential for interaction with and activating the FGFR-Klotho complex [16]. Between the N- and C-terminal domains is a proteolytic site (176 RXXR 179), and FGF23 is inactivated by subtilisin-like proprotein convertase and plasminogen activators, resulting in two inactive N- and active C-terminal fragments [10, 21, 23, 22, 43, 72, 90, 102]. The C-terminal fragment can competitively interfere the formation of intact FGF23/αKlotho/FGFR complex, thus acting as a natural FGF23 antagonist [34].…”

Section: Fgf23 Fgfrs αKlotho Expression and Regulationmentioning

confidence: 99%

Role of αKlotho and FGF23 in regulation of type II Na-dependent phosphate co-transporters

Shi

Moe

2018

Pflugers Arch - Eur J Physiol

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Alpha-Klotho is a member of the Klotho family consisting of two other single-pass transmembrane proteins- βKlotho and γKlotho; only αKlotho has been shown to circulate in the blood. Fibroblast growth factor (FGF)23 is a member of the FGF superfamily of 22 genes/proteins. αKlotho serves as a co-receptor with FGF receptors (FGFRs) to provide a receptacle for physiological FGF23 signaling including regulation of phosphate metabolism. The extracellular domain of transmembrane αKlotho is shed by secretases and released into blood circulation (soluble αKlotho). Soluble αKlotho has both FGF23-independent and dependent roles in phosphate homeostasis by modulating intestinal phosphate absorption, urinary phosphate excretion, and phosphate distribution into bone in concerted interaction with other calciophosphotropic hormones such as PTH, and 1,25-(OH)2D. The direct role of αKlotho and FGF23 in maintenance of phosphate homeostasis is partly mediated by modulation of type II Na+dependent phosphate cotransporters in target organs. αKlotho and FGF23 are principal phosphotropic hormones and the manipulation of the αKlotho-FGF23 axis is a novel therapeutic strategy for genetic and acquired phosphate disorders and for conditions with FGF23 excess and αKlotho deficiency such as chronic kidney disease.

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PAI-1 is a critical regulator of FGF23 homeostasis

Abstract: Pharmacological inhibition of PAI-1 augments proteolytic clearance of FGF23.

Cited by 27 publications

References 52 publications

Regulation of fibroblast growth factor 23 (FGF23) in health and disease

Regulation of fibroblast growth factor 23 (FGF23) in health and disease

Targeting of plasminogen activator inhibitor-1 activity promotes elimination of chronic myeloid leukemia stem cells

Role of αKlotho and FGF23 in regulation of type II Na-dependent phosphate co-transporters

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