Parathyroid-Specific Deletion of Klotho Unravels a Novel Calcineurin-Dependent FGF23 Signaling Pathway That Regulates PTH Secretion

Olauson, Hannes; Lindberg, Karolina; Amin, Risul; Sato, Tadatoshi; Jia, Ting; Goetz, Regina; Mohammadi, Moosa; Andersson, Göran; Lanske, Beate; Larsson, Tobias E.

doi:10.1371/journal.pgen.1003975

Cited by 149 publications

(130 citation statements)

References 35 publications

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“…17) In addition, Fgf23 was recently shown to inhibit the secretion of parathyroid hormones from parathyroid glands, both in α Klotho-dependent and -independent manners. 23) Our present data suggested that the activation of Fgf receptor by Fgf23 is essential for the activity of Fgf23 in macrophages. Therefore, Fgf23 increases the number of macrophages and induces the expression of TNF-α via the signaling of Fgf receptor in an α Klotho-independent manner.…”

supporting

confidence: 52%

Expression of Fgf23 in Activated Dendritic Cells and Macrophages in Response to Immunological Stimuli in Mice

Masuda

Ohta

Morita

et al. 2015

Biological & Pharmaceutical Bulletin

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Fibroblast growth factors (Fgfs) are polypeptide growth factors with diverse biological activities. While several studies have revealed that Fgf23 plays important roles in the regulation of phosphate and vitamin D metabolism, the additional physiological roles of Fgf23 remain unclear. Although it is believed that osteoblasts/osteocytes are the main sources of Fgf23, we previously found that Fgf23 mRNA is also expressed in the mouse thymus, suggesting that it might be involved in the immune system. In this study we examined the potential roles of Fgf23 in immunological responses. Mouse serum Fgf23 levels were significantly increased following inoculation with Escherichia coli or Staphylococcus aureus or intraperitoneal injection of lipopolysaccharide. We also identified activated dendritic cells and macrophages that potentially contributed to increased serum Fgf23 levels. Nuclear factor-kappa B (NF-κB) signaling was essential for the induction of Fgf23 expression in dendritic cells in response to immunological stimuli. Moreover, we examined the effects of recombinant Fgf23 protein on immune cells in vitro. Fgfr1c, a potential receptor for Fgf23, was abundantly expressed in macrophages, suggesting that Fgf23 might be involved in signal transduction in these cells. Our data suggest that Fgf23 potentially increases the number in macrophages and induces expression of tumor necrosis factor-α (TNF-α), a proinflammatory cytokine. Collectively, these data suggest that Fgf23 might be intimately involved in inflammatory processes.Key words fibroblast growth factor (Fgf); Fgf23; macrophage; dendritic cell; inflammationThe fibroblast growth factors (Fgfs) family consists of 22 polypeptide growth factors that are widely expressed in developing and adult tissues and regulate diverse biological processes, including angiogenesis, mitogenesis, cellular differentiation, and tissue repair. 1,2) Fgfs can be classified into three groups, canonical, intracellular, and hormone-like Fgfs. The canonical Fgfs bind to and activate Fgf receptors (Fgfrs) on the cell surface, resulting in the activation of several cytoplasmic signal transduction pathways. These canonical Fgfs function in a paracrine manner. The intracellular Fgfs act as intracellular signaling molecules in an Fgfr-independent manner. Hormone-like Fgfs, including Fgf15/19, Fgf21, and Fgf23, depends on Fgfrs to elicit biological responses, although they potentially function in an endocrine manner. 3) One of these hormone-like Fgfs, Fgf23, was originally identified in mice and humans by a DNA database search and was a well-known physiological regulator of phosphate and vitamin D metabolisms. [3][4][5][6] Fgf23 is produced by osteoblasts/osteocytes in response to 1,25-dihydroxyvitamine D, the biologically active form of vitamin D. 3,5,6) Secreted Fgf23 increases urinary phosphate excretion by reducing luminal expression of sodium-phosphate co-transporters in the proximal tubule. Secreted Fgf23 also attenuates systemic levels of 1,25-dihydroxyvitamine D, which stimulates phosphate...

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supporting

confidence: 52%

Expression of Fgf23 in Activated Dendritic Cells and Macrophages in Response to Immunological Stimuli in Mice

Masuda

Ohta

Morita

et al. 2015

Biological & Pharmaceutical Bulletin

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“…Providing only the cKL form in a sustained manner created the ability to test this factor's activity and pharmacologic potential in the absence of mKL in an environment of hyperphosphatemia. Similar to mice conditionally lacking parathyroid aKL expression, aKLnull mice may maintain low parathyroid hormone (PTH) levels by using an aKL-independent calcineurin-mediated FGF23 signaling pathway to suppress the secretion of PTH, 53 which could occur, in part, with the known negative feedback loop between 1,25D and PTH. Indeed, we showed that cKL, likely through the elevated FGF23, reduced serum 1,25D in WT mice, leading to hyperparathyroidism.…”

Section: Discussionmentioning

confidence: 99%

Chronic Hyperphosphatemia and Vascular Calcification Are Reduced by Stable Delivery of Soluble Klotho

Hum

O’Bryan²,

Tatiparthi

et al. 2016

JASN

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aKlotho (aKL) regulates mineral metabolism, and diseases associated with aKL deficiency are characterized by hyperphosphatemia and vascular calcification (VC). aKL is expressed as a membrane-bound protein (mKL) and recognized as the coreceptor for fibroblast growth factor-23 (FGF23) and a circulating soluble form (cKL) created by endoproteolytic cleavage of mKL. The functions of cKL with regard to phosphate metabolism are unclear. We tested the ability of cKL to regulate pathways and phenotypes associated with hyperphosphatemia in a mouse model of CKD-mineral bone disorder and aKL-null mice. Stable delivery of adeno-associated virus (AAV) expressing cKL to diabetic endothelial nitric oxide synthase-deficient mice or aKL-null mice reduced serum phosphate levels. Acute injection of recombinant cKL downregulated the renal sodium-phosphate cotransporter Npt2a in aKL-null mice supporting direct actions of cKL in the absence of mKL. aKL-null mice with sustained AAV-cKL expression had a 74%-78% reduction in aorta mineral content and a 72%-77% reduction in mineral volume compared with control-treated counterparts (P,0.01). Treatment of UMR-106 osteoblastic cells with cKL + FGF23 increased the phosphorylation of extracellular signal-regulated kinase 1/2 and induced Fgf23 expression. CRISPR/Cas9-mediated deletion of fibroblast growth factor receptor 1 (FGFR1) or pretreatment with inhibitors of mitogen-activated kinase kinase 1 or FGFR ablated these responses. In summary, sustained cKL treatment reduced hyperphosphatemia in a mouse model of CKD-mineral bone disorder, and it reduced hyperphosphatemia and prevented VC in mice without endogenous aKL. Furthermore, cKL stimulated Fgf23 in an FGFR1-dependent manner in bone cells. Collectively, these findings indicate that cKL has mKL-independent activity and suggest the potential for enhancing cKL activity in diseases of hyperphosphatemia with associated VC.

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“…Klotho activity has also been implicated as fundamental for the stimulation of PTH secretion during hypocalcaemic conditions (Imura et al 2007), although the underlying mechanism has been challenged (Martuseviciene et al 2011). An in vitro study has demonstrated that blocking a parathyroid-FGF23 signalling pathway, involving calcineurin, led to abolition of FGF23-induced suppresion of PTH secretion (Olauson et al 2013). Thus, this pathway could be another future molecular target pathway for the treatment of parathyroid carcinoma.…”

Section: Molecular Targeted Treatmentmentioning

confidence: 99%

Molecular targeted therapies in adrenal, pituitary and parathyroid malignancies

Angelousi¹,

Dimitriadis²,

Zografos³

et al. 2017

Endocrine-Related Cancer

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Tumourigenesis is a relatively common event in endocrine tissues. Currently, specific guidelines have been developed for common malignant endocrine tumours, which also incorporate advances in molecular targeted therapies (MTT), as in thyroid cancer and in gastrointestinal neuroendocrine malignancies. However, there is little information regarding the role and efficacy of MTT in the relatively rare malignant endocrine tumours mainly involving the adrenal medulla, adrenal cortex, pituitary, and parathyroid glands. Due to the rarity of these tumours and the lack of prospective studies, current guidelines are mostly based on retrospective data derived from surgical, locoregional and ablative therapies, and studies with systemic chemotherapy. In addition, in many of these malignancies the prognosis remains poor with individual patients responding differently to currently available treatments, necessitating the development of new personalised therapeutic strategies. Recently, major advances in the molecular understanding of endocrine tumours based on genomic, epigenomic, and transcriptome analysis have emerged, resulting in new insights into their pathogenesis and molecular pathology. This in turn has led to the use of novel MTTs in increasing numbers of patients. In this review, we aim to present currently existing and evolving data using MTT in the treatment of adrenal, pituitary and malignant parathyroid tumours, and explore the current utility and effectiveness of such therapies and their future evolution.

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Parathyroid-Specific Deletion of Klotho Unravels a Novel Calcineurin-Dependent FGF23 Signaling Pathway That Regulates PTH Secretion

Cited by 149 publications

References 35 publications

Expression of Fgf23 in Activated Dendritic Cells and Macrophages in Response to Immunological Stimuli in Mice

Expression of Fgf23 in Activated Dendritic Cells and Macrophages in Response to Immunological Stimuli in Mice

Chronic Hyperphosphatemia and Vascular Calcification Are Reduced by Stable Delivery of Soluble Klotho

Molecular targeted therapies in adrenal, pituitary and parathyroid malignancies

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