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Phosphate homeostasis is a complex process involving communication among bones, kidneys, and other organ systems.1, 2 This is tightly regulated through parathyroid hormone (PTH) and bone-derived fibroblast growth factor 23 (FGF23).1, 2, 3 Disruption of either pathway has been associated with a number of disorders resulting in hypo- or hyperphosphatemia.1 These disorders tend to have profound effects on the human body through demineralization or ectopic calcifications/stone production.1  The role of PTH in phosphate regulation has been well described.4 Hypocalcemia or hyperphosphatemia stimulates the release of PTH from the parathyroid glands. Within the kidney, PTH activates vitamin D and downregulates phosphate reabsorption. Activated 1,25-hydroxyvitamin D then has an effect on the gastrointestinal tract and promotes phosphate and calcium absorption.1, 2, 3, 4 With the elucidation of the FGF23 pathway, phosphate regulation has now been further clarified (Figure 1).5 FGF23 is released from bone during periods of hyperphosphatemia or elevated PTH or 1,25 hydroxyvitamin D levels.5, 6 Within the kidney, FGF23, in conjunction with its critical co-receptor Klotho, decreases reabsorption of phosphate and inhibits conversion of 25-hydroxyvitamin D to 1,25 hydroxyvitamin D by 1α-hydroxylase.6 It also inhibits PTH release from the parathyroid glands, thereby regulating both PTH and vitamin D.4 Loss of FGF23 function on target organs results in increased phosphate reabsorption and decreased excretion from the kidneys, leading to hyperphosphatemia, higher levels of 1,25-hydroxyvitamin D, and low levels of 25-hydroxyvitamin D as a result of consumption caused by unregulated conversion and reduced PTH secretion from the parathyroid glands.4, 5, 6Open in a separate window   Figure 1   Fibroblast growth factor 23 (FGF23) signaling pathway. FGF23 is induced by hyperphosphatemia, increased parathyroid hormone (PTH), and increased activated vitamin D. After it acquires protection from proteolysis before secretion by GALNT3, FGF23 signaling relies on the FGF receptor (FGFR) and its co-receptor Klotho. Activation of the FGFR leads to the inhibition of the sodium-phosphate cotransporter (Na-Pi-2a), leading to decreased phosphate reabsorption. FGFR-Klotho also inhibits the conversion of 25-hydroxyvitamin D to 1,25 hydroxyvitamin D, leading to decreased activated vitamin D. Not shown here are FGF23’s actions on the parathyroid gland where it decreases PTH secretion as well. Na, sodium; Phos, phosphorus.

A Case of Hyperphosphatemia and Elevated Fibroblast Growth Factor 23: A Brief Review of Hyperphosphatemia and Fibroblast Growth Factor 23 Pathway