Abstract 13727: A Protective Role of Fibroblast Growth Factor 23 Against Vascular Calcification
Introduction: Fibroblast growth factor 23 (FGF23) has been postulated to be involved in vascular calcification. However, both clinical and basic research demonstrated conflicting evidence indicating either a protective or harmful effect of FGF23 on vasculature.
Aim: The aim of this study was to determine the role of FGF23 in the development of the vascular calcification.
Methods and Results: In 60 consecutive patients, serum FGF23 levels and coronary artery calcium scores (CCS) were assessed. Serum FGF23 levels were significantly elevated in patients with CCS≧100 U compared with those with lower CCS (p<0.01). FGF23 levels were positively correlated with osteoprotegerin (OPG), a decoy receptor for RANKL (r=0.65, p<0.01). In vitro experiments using cultured human aortic smooth muscle cells (HASMC) showed the abundant expression of the Klotho, a co-receptor for FGF23, and the FGF receptors 1-4 as determined by RT-PCR, while no expression of the Klotho gene was detected in human aortic endothelial cells (HAEC). Western blot analyses revealed that recombinant FGF23 (rFGF23) stimulated ERK phosphorylation and Egr-1 expression in HASMC. Real-time PCR of mRNA prepared from HASMC transduced with adenovirus expressing human FGF23 (Ad-FGF23) showed that FGF23 blocked phosphate (Pi)-induced expression of the osteoblast-marker genes including BMP2, Msx2, Runx2 and alkaline phosphatase (ALP) in HASMC, but not FGF23-expressing HAEC. In addition, Ad- FGF23 promoted OPG mRNA expression and protein secretion in HASMC. Consistently, beta glycerophosphate (βGP)-induced ALP activity was markedly attenuated in HASMC transduced with Ad-FGF23. Furthermore, real-time PCR demonstrated that adenovirus-mediated overexpression of Klotho and conditioned medium of the cells overexpressing FGF23 significantly up-regulated OPG expression in HASM. Interestingly, rFGF23 induced the expression of Egr-1 and SP1, which binding site are located within the OPG promoter.
Conclusions: These data demonstrate that FGF23 induces OPG expression and negatively regulates osteogenic differentiation of HASMC. These findings lend support to the hypothesis that FGF23/Klotho signaling prevents vascular SMC from phosphorus, a direct vascular toxin
- © 2013 by American Heart Association, Inc.