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