Abstract
Fibroblast growth factor 23 (FGF-23) is likely to be the most important regulator of phosphate homeostasis, which mediates its functions through FGF receptors and the coreceptor Klotho. Besides reducing expression of the sodium-phosphate cotransporters NPT2a and NPT2c in the proximal tubules, FGF-23 inhibits the renal 1α-hydroxylase and stimulates the 24-hydroxylase, and it appears to reduce parathyroid hormone (PTH) secretion in short-term studies. FGF-23 synthesis and secretion by osteocytes and osteoblasts is upregulated through 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] and through an increased dietary phosphate intake. FGF-23 levels are elevated or inappropriately normal in patients with tumor-induced osteomalacia and several inherited hypophosphatemic disorders, but the most significant increases are found in patients with chronic kidney disease (CKD). During the early stages of CKD, increased FGF-23 production enhances urinary phosphate excretion and thus prevents the development of hyperphosphatemia, reduces the circulating levels of 1,25(OH)2D3, and therefore contributes to the development of secondary hyperparathyroidism. In patients with end-stage renal disease (ESRD), FGF-23 levels can be extremely high and were shown to be predictors of bone mineralization, left ventricular hypertrophy, vascular calcification, and mortality. It remains to be determined, however, whether FGF-23 represents simply a sensitive biomarker of an abnormal phosphate homeostasis or has, independent of serum phosphate levels, potentially negative “off-target” effects. Nonetheless, reducing the production and/or the biologic activity of FGF-23 may be an important therapeutic goal for this patient population. © 2010 American Society for Bone and Mineral Research.
Highlights
Parathyroid hormone (PTH) and active vitamin D metabolites are the most important regulators of calcium homeostasis, and much knowledge regarding their mode of actions has accumulated over several decades.[1,2,3] PTH affects phosphate homeostasis through its actions on kidney and bone, whereas 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], which is generated from the precursor 25-hydroxyvitamin D through the renal 1a-hydroxylase, contributes to intestinal phosphate absorption.[3] both hormones are not the only and probably not the most important hormonal regulators of phosphate homeostasis
SS 2010 American Society for Bone and Mineral Research disease (ESRD) treated with dialysis, fibroblast growth factor 23 (FGF-23) levels were associated with abnormal bone metabolism.[10] left ventricular hypertrophy and mass index,(11) vascular calcifications,(12) and increased mortality.[13,14] FGF-23 appears to have an important role as a biomarker in chronic kidney disease (CKD) patients, and measuring FGF-23 levels is likely to provide a sensitive diagnostic tool for assessing phosphate homeostasis and possibly its detrimental ‘‘off-target’’ effects
The elevation in serum FGF-23 levels in CKD stages 2 and 3 most likely precedes the increase in PTH levels, raising the possibility that secondary hyperparathyroidism develops, at least in part, because of an FGF-23-induced reduction in the renal production of 1,25(OH)2D3, an important negative regulator of PTH synthesis.[55,56] On the other hand, FGF-23 was shown in short-term studies to directly reduce the secretion of PTH in vitro and in vivo,(57,58) suggesting that FGF-23 has two competing effects on PTH synthesis and/or secretion—an indirect effect through an FGF-23-dependent reduction in 1,25(OH)2D3 synthesis and a direct effect on parathyroid cells, which express different FGF receptors as well as Klotho and can bind FGF-23 with high affinity
Summary
Parathyroid hormone (PTH) and active vitamin D metabolites are the most important regulators of calcium homeostasis, and much knowledge regarding their mode of actions has accumulated over several decades.[1,2,3] PTH affects phosphate homeostasis through its actions on kidney and bone, whereas 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], which is generated from the precursor 25-hydroxyvitamin D through the renal 1a-hydroxylase, contributes to intestinal phosphate absorption.[3].
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
