Fibroblast Growth Factor 23

Fibroblast growth factor 23 (FGF-23), a member of the fibroblast growth factor (FGF) family of proteins, is a phosphaturic hormone predominantly produced by bone osteocytes.^2-7 Plasma FGF-23 exerts its actions by binding to the FGF receptors on cell membranes. Effective FGF-23 binding to these cell surface receptors requires that the cell membrane also contain the transmembrane protein, Klotho.^2,8-11 FGF-23 inhibits phosphate reabsorption by suppressing Na/Pi cotransporter activity in the proximal convoluted tubule of the kidney. In addition, FGF-23 suppresses intestinal phosphate absorption by inhibiting 1-α-hydroxylase, the enzyme responsible for the conversion of calcifediol to calcitriol, the biologically active form of vitamin D.^2-4 FGF-23 also possibly inhibits parathyroid hormone (PTH) synthesis and secretion.^1-9 In healthy individuals, low levels of FGF-23 are detected in the circulation, and FGF-23 secretion rises with increased phosphorus intake and increased calcitriol levels.¹²

Elevated plasma FGF-23 activity has been associated with several hypophosphatemic diseases characterized by impaired renal phosphate reabsorption and rickets/osteomalacia.^5,6,9 Mutations in FGF-23 that render the protein resistant to proteolytic cleavage lead to increased FGF-23 activity and the renal phosphate loss found in autosomal-dominant hypophosphatemic rickets (ADHR). X-linked hypophosphatemic rickets (XLH)^5,6,9 and autosomal-recessive hypophosphatemic rickets (ARHR) are due to mutations in PHEX and dentin matrix protein 1, respectively. Both disorders are characterized by overproduction of FGF-23 by bone osteocytes. In tumor-induced osteomalacia (TIO), an acquired disorder of renal phosphate wasting associated with tumors, typically of mesenchymal origin; phosphatonins produced by the tumor promote renal phosphate wasting. FGF-23 is the most common phosphatonin found in patients with TIO.⁵ Patients with TIO share similar biochemical and skeletal phenotypes with patients who have ADHR, ARHR, and XLH.⁵

FGF-23 levels increase dramatically as renal function declines in chronic kidney disease (CKD) as the body attempts to overcome persistent phosphate retention.^2,4 FGF-23 elevation is thought to play a role in causing the disordered bone and mineral metabolism seen in CKD patients.^2,4 FGF-23 levels increase in parallel with the decline in renal function well before a significant increase in serum phosphate concentration or PTH occur.^2,4 Increased FGF-23 levels lead to reduced renal production of 1,25-dihydroxyvitamin D and to hypersecretion of parathyroid hormone.³ Prospective studies have demonstrated that elevated FGF-23 levels predict faster disease progression in CKD patients not on dialysis and increased mortality in patients undergoing maintenance hemodialysis and patients with renal transplants.^2,13 FGF-23 may predict future development of refractory hyperparathyroidism and cardiovascular events in CKD patients^3,14 and is thought to play a central role in the pathogenesis of post-transplant hypophosphatemia in kidney transplant recipients.³