Fibroblast Growth Factor, A Review

Abstract

The recent identification of fibroblast growth factor (FGF)23 has filled in the gaps of our understanding of calcium– phosphate regulation. Together with its cofactor Klotho, FGF-23 is a phosphaturic factor that influences vitamin D metabolism and renal re-absorption of phosphorus in order to maintain serum phosphate levels within the normal range. In chronic kidney disease (CKD), FGF-23 levels rise in parallel with declining kidney function before any significant rise is perceived in serum phosphate concentration. Increased serum FGF-23 levels in CKD patients were found to be independently associated with ventricular hypertrophy and endothelial dysfunction after correcting for traditional markers of calcium–phosphate metabolism. FGF-23 has been implicated in various human diseases including autosomal dominant hypophosphatemic rickets (ADHR), X-linked hypophosphatemia (XLH), tumor induced osteomalacia and familial tumoral calcinosis. Lastly, in prospective studies, elevated serum FGF-23 levels predicted rapid disease progression in non-dialysis dependent CKD patients and increased mortality in chronic hemodialysis patients. The growing knowledge and understanding of FGF-23 may provide potential answers with regards to prevention and management of CKD [1]. The FGF family is comprised of polypeptides that share a common region of amino peptide residues. Seven human FGF subfamilies have been identified; FGF-23 belongs to the FGF19 subgroup including FGF 19, 21 and 23 having very different physiological functions despite sharing a similar disulphide bond which is absent in most other families. FGF23 is a central regulator of phosphate homeostasis, enhancing phosphorus excretion and suppressing1-alpha hydroxylase activity in the kidney [2, 3], whereas FGF-19 is involved in bile acid synthesis and FGF-21 stimulates insulinindependent glucose uptake in adipocytes and reduces triglyceride levels. The active form of FGF-23 is an approximately 32-kD (251 amino acids) protein with its gene located on chromosome 12 [4, 5]. It is mainly expressed in osteocytes [6, 7], and also expressed in pericyte-like cells around the venous sinuses, the ventrolateral thalamic nucleus, and in the thymus. The contribution of sites other than bone to circulating FGF-23 levels is still unclear. It is clear, however that there are high levels of expression in the osteocytes and that because osteocytes are the most abundant cell in bone, this suggests that the serum levels of FGF-23 are derived mainly from bone [8]. FGF-23 exerts its biological effects through activation of FGF receptors in a Klotho dependent manner, as a Klotho/ FGF-Receptor complex binds to FGF-23. Klotho is a transmembrane protein, the gene expression of which was detected in distal renal tubular cells, parathyroid gland, the pituitary gland, ovary, testis, skeletal muscle, duodenum, pancreas and choroid plexus. It is unclear why Klotho is G. C. Chibesakunda (*) :C. S. Brecklin Department of Medicine/Section of Nephrology, University of Illinois Medical Center at Chicago, 820 S Wood Street (MC 793), Chicago, IL 60612, USA e-mail: gracecc@uic.edu