Clinical Information

Fibroblast growth factor 23 (FGF23) is a major regulator of phosphate homeostasis. It may act in concert with several other less well-characterized phosphate regulators.

FGF23 is secreted primarily by bone, followed by thymus, heart, brain and, in low levels, by several other tissues. It is coexpressed with the X-linked phosphate-regulating endopeptides (PHEX). High serum phosphate levels stimulate FGF23 expression and secretion through as yet poorly understood mechanisms. PHEX appears to modulate this process, possibly in part through cleavage of FGF23. Only intact FGF23 is considered bioactive. It interacts with a specific receptor on renal tubular cells, decreasing expression of type IIa sodium/phosphate cotransporters, resulting in decreased phosphate reabsorption. In addition, gene transcription of 1-a-hydroxylase is downregulated, reducing bioactive 1,25-dihydroxy vitamin D (1,25-2OH-VitD), thereby further decreasing phosphate reabsorption. Eventually, falling serum phosphate levels lead to diminished FGF23 secretion, closing the feedback loop.

Measurement of FGF23 can assist in diagnosis and management of disorders of phosphate and bone metabolism in patients with either normal or impaired renal function. When FGF23 levels are pathologically elevated in individuals with normal renal function, hypophosphatemia, with or without osteomalacia, ensues. This can occur with rare, usually benign, mixed connective tissue tumors that contain characteristic complex vascular structures, osteoclast-like giant cells, cartilaginous elements, and dystrophic calcifications. These neoplasms secrete FGF23 ectopically and autonomously (oncogenic osteomalacia). In less than one-fourth of cases a different benign or malignant, soft tissue tumor type, or, extremely rarely, a carcinoma, may be the cause of paraneoplastic FGF23 secretion. In either scenario, complete removal of the tumor cures the oncogenic osteomalacia.

Hypophosphatemia and skeletal abnormalities are also observed in X-linked hypophosphatemia (XLH) and autosomal dominant hypophosphatemic rickets (ADHR). In XLH, mutations of PHEX reduce its negative modulatory effect on bioactive FGF23 secretion. In ADHR, FGF23 mutations render it resistant to proteolytic cleavage, thereby increasing FGF23 levels. However, not all FGF23 mutations increase renal phosphate secretions. Mutations that impair FGF23 signaling, rather than increase its protease resistance, are associated with the syndrome of familial tumoral calcinosis (ectopic calcifications) with hyperphosphatemia.

In patients with renal failure, FGF23 contributes to renal osteodystrophy. The patient's kidneys can no longer excrete sufficient amounts of phosphate. This leads to marked increases in FGF23 secretions in a futile compensatory response, aggravating the 1,25-2OH-VitD deficiency of renal failure and the consequent secondary hyperparathyroidism.