Elsevier

Experimental Cell Research

Volume 318, Issue 9, 15 May 2012, Pages 1040-1048
Experimental Cell Research

Review Article
Role of FGF23 in vitamin D and phosphate metabolism: Implications in chronic kidney disease

https://doi.org/10.1016/j.yexcr.2012.02.027Get rights and content

Abstract

FGF23 is a bone-derived hormone that regulates systemic phosphate homeostasis, vitamin D metabolism and α-Klotho expression through a novel bone-kidney axis. FGF23 inhibits renal tubular reabsorption of phosphate through mechanisms independent of PTH as well as reduces circulating 1, 25(OH)2D through its dual effects to suppress Cyp27b1 production and to stimulate Cyp24 catabolism of 1,25(OH)2D. 1,25(OH)2D and other factors regulating bone remodeling/mineralization are the major physiological regulators of FGF23 expression. FGF23 also suppresses the gene transcription of α-klotho by the kidney, which exists as a membrane and soluble protein. Membrane Klotho acts as a coreceptor for and dictates organ specificity of FGF23, whereas soluble Klotho act as an endocrine factor that regulates activity of cell surface glycoproteins and receptors in multiple tissues. Elevated FGF23 levels are responsible for several hereditary and acquired hypophosphatemic rickets disorders. FGF23 and Klotho deficiency have similar phenotypes characterized by hyperphosphatemia, elevated 1,25(OH)2D and tumoral calcinosis. FGF23 levels progressively increase during chronic kidney disease (CKD). FGF23 has been proposed to be the initial adaptive response leading to reductions in 1,25(OH)2D and secondary hyperparathyroidism (HPT) in CKD. The overall biological effect of this initial step may be to orchestrate a coordinated adaptation to protect the organism from the adverse effects of excess phosphate retention. The second step involves the effects of PTH on bone remodeling that further stimulates FGF23 production through both direct and indirect mechanisms related to alterations in extracellular matrix factors. PTH further amplifies FGF23 expression in later stages of CKD to compensate for the increased phosphate efflux from bone caused by excessive bone turnover. While many aspects of the regulation and functions of FGF23 remain to be established, the idea that FGF23 hormone is the initial adaptive hormonal response in CKD that suppresses 1,25(OH)2D, reduces gastrointestinal calcium and phosphate absorption and leads to a secondary HPT represents a paradigm shift in the conceptualization of the pathogenesis of secondary hyperparathyroidism. In addition, the prevalent thought that CKD is a functional “vitamin D deficient state” requiring therapy with 1,25(OH)2D analogs is challenged by effects of FGF23 to potentially lower both 25(OH)D and 1,25(OH)D by induction of Cyp24-mediated degradation. Finally, increments in FGF23 are associated with increased cardiovascular mortality in CKD. Whether these effects represent direct effects of FGF23 or represent a marker of other abnormalities in CKD remains to be determined.

Section snippets

Overview of FGF23

FGF23 is a ~ 32 kDa secreted protein, predominately expressed in osteoblasts and osteocytes [45], [51], [84], [103], that principally targets receptor complexes consisting of FGFR 1,3 or 4 and the transmembrane β glucuoronidase,α-Kl [37], [43], [92], [105] in the kidney to inhibit renal phosphate reabsorption by decreasing Na-dependent co-transporters and to suppress circulating 1,25(OH)2D levels by inhibiting Cyp27b1 (which converts 25(OH)D to 1,25(OH)2D) and by stimulating the catabolism of

Physiological regulation FGF23

FGF23 is regulated by both systemic and local factors. FGF23 acts as a counter regulatory factor for 1,25(OH)2D [49] and participates in a bone-kidney feedback loop, consisting of 1,25(OH)2D stimulation of FGF23 production in bone and FGF23 suppression of 1,25(OH)2D production by the kidney [49]. A less well characterized feedback loop exists that involves stimulation of FGF23 expression in bone when FGF23 signaling in the kidney is blocked either through ablation of FGFR or α-Kl [50], [92].

Physiological functions of FGF23

Excess FGF23 causes hypophosphatemia, suppression of 1,25(OH)2D, and rickets/osteomalacia [2], [15], [39], [78], [80]. Loss of Fgf23 function results in hyperphosphatemia, excess 1,25(OH)2D, and soft tissue calcifications [6], [28], [38], [51], [77], [82], [83]. FGF23 regulation of cellular function in target tissues is mediated by binding to FGF receptor/Klotho complexes. α-Klotho is an obligate co-receptor for FGF23 and the tissue restricted actions of FGF23 are dictated by the sites of the

Role of FGF23 in CKD–mineral bone disorder (CKD–MBD)?

The pathogenesis of CKD is traditionally viewed from the perspective of the PTH-Vitamin D axis, and current treatments focus on suppressing PTH with active vitamin D analogs [99], which can raise serum calcium and phosphate concentrations [89] and further stimulate FGF23 [7], [19], [65], [104]. Cross-sectional studies in humans show early FGF23 elevations in CKD in proportion to reduced GFR [18] and is associated with reductions of 1,25(OH)2D and increments in Cyp24 [20]. FGF23 is markedly

Integrated hypothesis of FGF23 regulation and function in CKD (Fig. 1)

A two-step hypothesis may reconcile the conflicting data regarding the respective roles of FGF23 and PTH in the pathogenesis of abnormal mineral metabolism in CKD. The first part of the hypothesis integrates current knowledge of the FGF23–Vitamin D endocrine loop, whereas the later proposition incorporates emerging knowledge regarding the role of intrinsic bone matrix-derived factors in the regulation of FGF23. There is evidence to support that increased FGF23 (due to impaired renal phosphate

Revising the “vitamin D deficient” hypothesis of CKD-MBD pathogenesis

Contradictory and competing hypotheses and uncertainties about the cause-and-effect relationship between FGF23, PTH and 1,25(OH)2D are confounding the understanding of the pathogenesis and treatment of CKD-MBD. It makes a big difference whether FGF23 is the initial event leading to increased PTH or is secondary to increments in PTH. If the two step hypothesis is correct, it may be possible to separately focus interventions on different mechanisms leading to increased FGF23 at different stages

Summary and conclusions

The discovery of FGF23 expression by osteoblasts/osteocytes has revealed the “endocrine functions” of bone in the regulation of phosphate and vitamin D metabolism. In addition, bone may have other endocrine functions to regulate insulin secretion and glucose metabolism that are mediated by the release of decarboxylated osteocalcin (Ocn) by bone resorption. Ocn is proposed to target receptors, such as GPRC6A, located in β-cells and peripheral tissues to regulate insulin secretion and insulin

Acknowledgments

This work was supported by the NIH grant number 2RO1AR045955.

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