Overexpression of fibroblast growth factor 23 suppresses osteoblast differentiation and matrix mineralization in vitro.
BACKGROUND
Fibroblast growth factor (FGF)23 is produced primarily in bone and acts on kidney as a systemic phosphaturic factor; high levels result in rickets and osteomalacia. However, it remains unclear whether FGF23 acts locally and directly on bone formation.


METHODS
We overexpressed human FGF23 in a stage-specific manner during osteoblast development in fetal rat calvaria (RC) cell cultures by using the adenoviral overexpression system and analyzed its effects on osteoprogenitor proliferation, osteoid nodule formation, and mineralization. Bone formation was also measured by calcein labeling in parietal bone organ cultures. Finally, we addressed the role of tyrosine phosphorylation of FGF receptor (FGFR) in mineralized nodule formation.


RESULTS
Nodule formation and mineralization, but not osteoprogenitor proliferation, were independently suppressed by overexpression of FGF23 in RC cells. Increased FGF23 levels also suppressed bone formation in the parietal bone organ culture model. FGF23 overexpression enhanced phosphorylation of FGFR, whereas the impairment of mineralized nodule formation by FGF23 overexpression was abrogated by SU5402, an inhibitor of FGFR1 tyrosine kinase activity.


CONCLUSIONS
These studies suggest that FGF23 overexpression suppresses not only osteoblast differentiation but also matrix mineralization independently of its systemic effects on Pi homeostasis.
Wang
Hua
H
Oral Growth and Developmental Biology, Hiroshima University Graduate School of Biomedical Sciences, Hiroshima, Japan.
Yoshiko
Yuji
Y
Yamamoto
Ryoko
R
Minamizaki
Tomoko
T
Kozai
Katsuyuki
K
Tanne
Kazuo
K
Aubin
Jane E
JE
Maeda
Norihiko
N
D000818:Animals; D002113:Calcification, Physiologic; D002454:Cell Differentiation; D002478:Cells, Cultured; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D000089703:Fibroblast Growth Factor-23; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D010006:Osteoblasts / Q000166:cytology* / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D017468:Receptors, Fibroblast Growth Factor / Q000378:metabolism; D012886:Skull / Q000166:cytology / Q000378:metabolism; D046509:Tissue Culture Techniques
C000717427:FGF23 protein, human; D017468:Receptors, Fibroblast Growth Factor; D005346:Fibroblast Growth Factors; D000089703:Fibroblast Growth Factor-23