Parathyroid hormone activates the orphan nuclear receptor Nurr1 to induce FGF23 transcription
Open accessAbstract
Parathyroid hormone (PTH) increases FGF23 mRNA and protein levels in vivo and in vitro. Here we tested whether the increased FGF23 expression by PTH is mediated by the orphan nuclear receptor Nurr1. PTH increased Nurr1 mRNA levels prior to elevation of FGF23 mRNA levels in UMR-106 rat osteoblast-like cells. Activation of PKA increased both FGF23 and Nurr1 mRNA levels. Modification of Nurr1 expression showed that Nurr1 is essential for the PTH-mediated increase in FGF23 and luciferase reporter gene experiments identified a functional promoter region containing several potential Nurr1 binding sites. Chromatin immunoprecipitation assays confirmed the binding of Nurr1 to these regions in the FGF23 promoter. In vivo, Nurr1 mRNA and protein levels were increased in calvaria from rats with experimental CKD together with high PTH and FGF23 expression. Calcimimetics decrease PTH and FGF23 levels in CKD patients. Importantly, in rats with experimental CKD, the calcimimetic R568 decreased PTH expression, calvaria Nurr1 mRNA and protein levels, and FGF23 mRNA. Immunohistochemistry for Nurr1 showed an increase in the number of Nurr1 expressing osteocytes in the femurs of rats with CKD and this was decreased by R568. Thus, the effect of PTH to increase FGF23 transcription is mediated by Nurr1 in vitro and in vivo. In CKD, calcimimetics decrease PTH, which in turn decreases Nurr1 and consequently FGF23.
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In the current study, elevated iFGF23 did not inhibit PTH secretion but rather PTH stimulated iFGF23, eventually to lower plasma Pi.
“suggesting that in the current study elevated iFGF23 did not inhibit PTH secretion but rather PTH stimulated iFGF23, eventually to lower plasma Pi [4, 39].”
From Controlled dietary phosphate loading in healthy young men elevates plasma phosphate and FGF23 levels (2025) · cites this paper as [39]
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- Authors
- Meir, T., Durlacher, K., Pan, Z., Amir, G., Richards, W. G., Silver, J., & Naveh-Many, T.
- Affiliations
- Hadassah Medical Center (IL)
- Amgen (United States) (US)
- Venue
- Kidney International
- Publisher
- Elsevier BV
- Published
- 2014-12
- Volume
- 86
- Issue
- 6
- Pages
- 1106-1115
- ISSN
- 0085-2538 (ISSN-L)
- OpenAlex
- W2067490907
- Cited by
- 152
- References
- 52
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 8 · 2023: 8 · 2022: 14 · 2021: 15 · 2020: 15 · 2019: 19 · 2018: 15 · 2017: 16 · 2016: 12 · 2015: 16 · 2014: 2
- FWCI
- 12.12
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Kidney International (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Amgen
- Israel Science Foundation
- Topics
- Health Sciences › Medicine › Nephrology › Parathyroid Disorders and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
- Keywords
- parathyroid hormone, Nurr1, fibroblast growth factor 23, orphan nuclear receptor, transcriptional regulation, protein kinase A, calcimimetics, chronic kidney disease, osteocytes, osteoblast-like cells, calvaria
- MeSH terms
- Aniline Compounds, Animals, Cells, Cultured, Fibroblast Growth Factors, Colforsin, Male, Osteoblasts, Parathyroid Hormone, Phenethylamines, Promoter Regions, Genetic, Propylamines, RNA, Messenger, Skull, Transcription, Genetic, Gene Expression, Rats, Sprague-Dawley, Cyclic AMP-Dependent Protein Kinases, Rats, Gene Knockdown Techniques, Nuclear Receptor Subfamily 4, Group A, Member 1, Nuclear Receptor Subfamily 4, Group A, Member 2, Calcimimetic Agents
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