Fibroblast growth factor 23 inhibits osteoblastic gene expression and induces osteoprotegerin in vascular smooth muscle cells.
Elevated fibroblast growth factor 23 (FGF23) levels are associated with cardiovascular mortality in patients with chronic kidney disease. However, both clinical and basic research have demonstrated conflicting evidence regarding the pathophysiological role of FGF23 in vascular calcification. The aim of this study was to determine the role of FGF23 in the osteoblastic gene expression in vascular smooth muscle cells (SMCs).



We transduce human aortic SMCs (HASMCs) expressing klotho and FGF receptors with the adenovirus expressing human FGF23 (Ad-FGF23). We observed significant decreases in the expression of osteoblast-marker genes including BMP2, BMP4, MSX2, RUNX2 and ALP, as well as reduced calcification. Notably, Ad-FGF23 increased mRNA and protein levels of osteoprotegerin (OPG), and human OPG promoter was activated by FGF23. Moreover, in HASMCs overexpressing klotho, FGF23 upregulated OPG expression, whereas depletion of klotho by siRNA attenuated FGF23-induced OPG expression. Furthermore, in 73 consecutive patients with type 2 diabetes mellitus undergoing cardiac computed tomography to determine coronary calcium scores (CCSs), serum FGF23 levels were positively correlated with OPG independent of phosphate and estimated glomerular filtration rate (eGFR, r = 0.65, p < 0.01). Serum FGF23 levels were significantly elevated in patients with high CCSs (≧100) compared to those with low CCSs (<100).



Our in vitro results indicate that FGF23 suppresses osteoblastic gene expression and induces OPG expression in HASMCs. Together with our cross-sectional clinical assessment, the present study lends support to our hypothesis that FGF23 counteracts osteogenic conversion of vascular SMCs as a part of a compensatory mechanism to mitigate vascular calcification.
Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
Takehiro
T
Nakahara
Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan; Department of General Medicine, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan. Electronic address: kowasek@gunma-u.ac.jp.
Keiko
K
Kawai-Kowase
Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
Hiroki
H
Matsui
Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
Hiroaki
H
Sunaga
Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
Toshihiro
T
Utsugi
Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
Tatsuya
T
Iso
Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
Masashi
M
Arai
Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
Shouichi
S
Tomono
Department of Medicine and Biological Science, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.
Masahiko
M
Kurabayashi
D001011:Aorta / Q000378:metabolism*; D002114:Calcinosis; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D003430:Cross-Sectional Studies; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000097:blood*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005966:Glucuronidase / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D000090265:Klotho Proteins; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism*; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism; D053244:Osteoprotegerin / Q000097:blood*; D010710:Phosphates / Q000737:chemistry; D034741:RNA, Small Interfering / Q000378:metabolism; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000378:metabolism; D048490:raf Kinases / Q000378:metabolism
C000717427:FGF23 protein, human; D053244:Osteoprotegerin; D010710:Phosphates; D034741:RNA, Small Interfering; C506030:TNFRSF11B protein, human; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D048490:raf Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D005966:Glucuronidase; D000090265:Klotho Proteins
Fibroblast growth factor 23; Osteoblastic differentiation; Osteoprotegerin; Vascular calcification; Vascular smooth muscle cells