Article

Clinical practice. Fibroblast growth factor (FGF)23: a new hormone.

Bone and Mineral Disorders Clinic, Section of Pediatric Nephrology, Children's Mercy Hospitals and Clinics, University of Missouri at Kansas City School of Medicine, 2401 Gillham Road, Kansas City, MO 64108, USA.
European Journal of Pediatrics (Impact Factor: 1.98). 12/2010; 170(5):545-54. DOI: 10.1007/s00431-010-1382-5
Source: PubMed

ABSTRACT Until a decade ago, two main hormones were recognized as directly affecting phosphate homeostasis and, with that, bone metabolism: parathyroid hormone and 1,25(OH)(2) vitamin D (calcitriol). It was only a decade ago that the third major player hormone was found, linking gut, bone, and kidney. The physiologic role of fibrinogen growth factor (FGF)23 is to maintain serum phosphate concentration within a narrow range. Secreted from osteocytes, it modulates kidney handling of phosphate reabsorption and calcitriol production. Genetic and acquired abnormalities in FGF23 structure and metabolism cause conditions of either hyper-FGF23-manifested by hypophosphatemia, low serum calcitriol, and rickets/osteomalacia-or hypo-FGF23, expressed by hyperphosphatemia, high serum calcitriol, and extra-skeletal calcifications. In patients with chronic renal failure, FGF23 levels increase as kidney functions deteriorate and are under investigation to learn if the hormone actually participates in the pathophysiology of the deranged bone and mineral metabolism typical for these patients and, if so, whether it might serve as a therapeutic target. This review addresses the physiology and pathophysiology of FGF23 and its clinical applications.

0 Followers
  • [Show abstract] [Hide abstract]
    ABSTRACT: Fibroblast growth factor 23 (FGF23) is a circulating factor secreted by osteocytes that is essential for phosphate homeostasis. In kidney proximal tubular cells FGF23 inhibits phosphate reabsorption and leads to decreased synthesis and enhanced catabolism of 1,25-dihydroxyvitamin D3 (1,25[OH]2D3). Excess levels of FGF23 cause renal phosphate wasting and suppression of circulating 1,25(OH)2D3 levels and are associated with several hereditary hypophosphatemic disorders with skeletal abnormalities, including X-linked hypophosphatemic rickets (XLH) and autosomal recessive hypophosphatemic rickets (ARHR). Currently, therapeutic approaches to these diseases are limited to treatment with activated vitamin D analogues and phosphate supplementation, often merely resulting in partial correction of the skeletal aberrations. In this study, we evaluate the use of FGFR inhibitors for the treatment of FGF23-mediated hypophosphatemic disorders using NVP-BGJ398, a novel selective, pan-specific FGFR inhibitor currently in Phase I clinical trials for cancer therapy. In two different hypophosphatemic mouse models, Hyp and Dmp1-null mice, resembling the human diseases XLH and ARHR, we find that pharmacological inhibition of FGFRs efficiently abrogates aberrant FGF23 signaling and normalizes the hypophosphatemic and hypocalcemic conditions of these mice. Correspondingly, long-term FGFR inhibition in Hyp mice leads to enhanced bone growth, increased mineralization, and reorganization of the disturbed growth plate structure. We therefore propose NVP-BGJ398 treatment as a novel approach for the therapy of FGF23-mediated hypophosphatemic diseases. © 2013 American Society for Bone and Mineral Research.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 04/2013; 28(4). DOI:10.1002/jbmr.1810 · 6.59 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Introduction Vitamin D is essential for bone mineralization and for the subsequent maintenance of bone quality. Mineralization is part of hard callus formation and bone remodelling, processes, which are part of fracture healing. We provide a comprehensive review of the literature to summarize and clarify if possible, the cellular effects of vitamin D and its clinical involvement in the process of fracture healing in human. Material and methods We conducted a literature search in PubMed, Embase (OVID version), and Web of Science. Results A total of 75 in vitro and 30 in vivo studies were found with inconsistent results about the cellular effect of vitamin D on fracture involved inflammatory cells, cytokines, growth factors, osteoblasts, osteoclasts and on the process of mineralization. With only five in vitro studies performed on material derived from a fracture site and one in vivo study in fracture patients, the exact cellular role remains unclear. Seven studies investigated the circulating vitamin D metabolites in fracture healing. Although it appears that 25(OH)D and 24,25(OH)2D3 are not affected by the occurrence of a fracture, this might not be the case with serum concentrations of 1,25(OH)2D3. The potential clinical effect of vitamin D deficiency is only described in one case series en three case controlled studies. Where the results tend to show no effect of a vitamin D deficiency. No clinical studies were found investigating solely vitamin D supplementation. Two clinical studies found a positive effect of vitamin D supplementation and calcium, of increased bone mineral density or respectively increased fracture callus area at the fracture site. One study found indirect evidence that vitamin D and calcium promoted fracture healing. Conclusion Despite these results, and the presumed beneficial effect of vitamin D supplementation in deficient patients, clinical studies that address the effects of vitamin D deficiency or supplementation on fracture healing are scarce and remain inconclusive. We conclude that vitamin D has a role in fracture healing, but the available data are too inconsistent to elucidate how and in what manner.
    Bone 01/2014; · 4.46 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Vitamin D is essential for bone mineralization and for the subsequent maintenance of bone quality. Mineralization is part of hard callus formation and bone remodelling, processes, which are part of fracture healing. We provide a comprehensive review of the literature to summarize and clarify if possible, the cellular effects of vitamin D and its clinical involvement in the process of fracture healing in human. We conducted a literature search in PubMed, Embase (OVID version), and Web of Science. A total of 75 in vitro and 30 in vivo studies were found with inconsistent results about the cellular effect of vitamin D on fracture involved inflammatory cells, cytokines, growth factors, osteoblasts, osteoclasts and on the process of mineralization. With only five in vitro studies performed on material derived from a fracture site and one in vivo study in fracture patients, the exact cellular role remains unclear. Seven studies investigated the circulating vitamin D metabolites in fracture healing. Although it appears that 25(OH)D and 24,25(OH)2D3 are not affected by the occurrence of a fracture, this might not be the case with serum concentrations of 1,25(OH)2D3. The potential clinical effect of vitamin D deficiency is only described in one case series en three case controlled studies. Where the results tend to show no effect of a vitamin D deficiency. No clinical studies were found investigating solely vitamin D supplementation. Two clinical studies found a positive effect of vitamin D supplementation and calcium, of increased bone mineral density or respectively increased fracture callus area at the fracture site. One study found indirect evidence that vitamin D and calcium promoted fracture healing. Despite these results, and the presumed beneficial effect of vitamin D supplementation in deficient patients, clinical studies that address the effects of vitamin D deficiency or supplementation on fracture healing are scarce and remain inconclusive. We conclude that vitamin D has a role in fracture healing, but the available data are too inconsistent to elucidate how and in what manner.
    Bone 05/2014; 64. DOI:10.1016/j.bone.2014.04.026 · 4.46 Impact Factor