Abstract
The metabolic changes that occur in patients with chronic kidney disease (CKD) have a profound influence on mineral and bone metabolism. CKD results in altered levels of serum phosphate, vitamin D, calcium, parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF-23); the increased levels of serum phosphate, PTH and FGF-23 contribute to the increased cardiovascular mortality in affected patients. FGF-23 is produced by osteocytes and osteoblasts and acts physiologically in the kidney to induce phosphaturia and inhibit the synthesis of 1,25-dihydroxyvitamin D3. PTH acts directly on osteocytes to increase FGF-23 expression. In addition, the high levels of PTH associated with CKD contribute to changes in bone remodelling that result in decreased levels of dentin matrix protein 1 and the release of low-molecular-weight fibroblast growth factors from the bone matrix, which stimulate FGF-23 transcription. A prolonged oral phosphorus load increases FGF-23 expression by a mechanism that includes local changes in the ratio of inorganic phosphate to pyrophosphate in bone. Other factors such as dietary vitamin D compounds, calcium, and metabolic acidosis all increase FGF-23 levels. This Review discusses the mechanisms by which secondary hyperparathyroidism associated with CKD stimulates bone cells to overexpress FGF-23 levels.
Key Points
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Secondary hyperparathyroidism and increased serum fibroblast growth factor 23 (FGF-23) levels in chronic kidney disease (CKD) are intimately related; secondary hyperparathyroidism has a crucial role in increasing the expression of FGF-23
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Parathyroid hormone (PTH) increases FGF-23 expression in osteoblast-like cells in vitro by activating protein kinase A and Wnt signalling pathways
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The ratio of inorganic phosphate to pyrophosphate in the bone matrix is increased in CKD, which increases FGF-23 expression
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The loss of FGF-23 transcriptional inhibition by dentin matrix protein 1 and the release of low-molecular-weight fibroblast growth factors increase FGF-23 expression in CKD
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FGF-23 acts on the kidney to decrease 1,25-dihydroxyvitamin D3 (1,25[OH]2D3) synthesis, which contributes to the secondary hyperparathyroidism of CKD, whereas 1,25(OH)2D3 itself increases FGF-23 transcription
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The FGF-23-receptor complex, Klotho–fibroblast growth factor receptor 1, is downregulated in the parathyroid gland of patients with CKD, resulting in loss of FGF-23's ability to decrease PTH expression
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The authors' work is supported the Harold and Ethel Pupkewitz Fund for Renal Research and Amgen. T. Naveh-Many's work is also supported by the Israel Science Foundation.
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J. Silver wrote the article. J. Silver and T. Naveh-Many contributed equally to researching data for the article, discussions of the content, and review and/or editing of the manuscript before submission.
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J. Silver and T. Naveh-Many have received a research grant from Amgen. J. Silver has received honoraria and lecture fees from Amgen, Fresenius, KAI Pharmaceuticals, Shire, and Teva Pharmaceutical Industries.
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Silver, J., Naveh-Many, T. FGF-23 and secondary hyperparathyroidism in chronic kidney disease. Nat Rev Nephrol 9, 641–649 (2013). https://doi.org/10.1038/nrneph.2013.147
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DOI: https://doi.org/10.1038/nrneph.2013.147
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