Abstract 13896: Fibroblast Growth Factor 23 Inhibits Osteogenic Differentiation of Vascular Smooth Muscle Cells: A Protective Role Against Vascular Calcification?
Background: Bone-derived phosphaturic hormone fibroblast growth factor 23 (FGF23) has been postulated to be involved in vascular calcification. However, both clinical and basic researches have demonstrated conflicting evidence as to whether FGF-23 imparts protective or a harmful role on vasculature. Objectives: The aim of this study was to determine the role of FGF23 in the development of the vascular calcification.
Methods and Results: We examined the association between serum FGF23 levels and coronary artery calcification (CAC) in 60 patients with type 2 diabetes who underwent multi-detector computed tomography (MDCT). Results showed that serum FGF23 levels were significantly elevated in patients with CAC score ≧100 U compared with those with low CAC score <100 U (p<0.01). FGF23 levels were positively correlated with osteoprotegerin (OPG), a decoy receptor for RANKL (r=0.65, p<0.01). Next, we examined the effects of FGF23 on the osteogenic differentiation of vascular smooth muscle cells (VSMC). RT-PCR showed the abundant expression of the klotho gene, a coreceptor for FGF23, and the FGF receptors 1-4 genes in cultured human aortic smooth muscle cells (HASMC). Western blot analyses revealed that FGF23 stimulated ERK phosphorylation and Egr-1 expression in HASMC, indicating that MAP kinase/Egr-1 pathway is activated by FGF23 in HASMC. Quantitative RT-PCR analysis of mRNA prepared from HASMC transduced with adenovirus expressing human FGF23 showed that FGF23 blocked phosphate-induced expression of the osteoblast-marker genes including BMP2, Msx2, Runx2 and alkaline phosphatase (ALP). In contrast, mRNA expression of OPG and matrix gla protein (MGP), both of which serve as physiological inhibitors for osteogenesis, was significantly up-regulated by FGF23. Enzyme-linked immunosorbent assay showed that OPG secretion was markedly increased in HASMC expressing FGF23. ALP activity, induced by Beta glycerophosphate (βGP), was markedly decreased in HASMC expressing hFGF23 cotroling by HASMC expressing LacZ.
Conclusions: These data demonstrate that FGF23 negatively regulates osteogenic differentiation of VSMC and lend support to the hypothesis that FGF23/Klotho signaling prevents vasculature from phosphorus, a direct vascular toxin.
- © 2012 by American Heart Association, Inc.