A protective role for FGF-23 in local defence against disrupted arterial wall integrity?

•FGF-23 expression was up-regulated in calcifying murine VSMCs and in calcified aortic Enpp1−/− mouse tissue.•Reduced calcium deposition was observed in calcifying VSMCs cultured with recombinant FGF-23.•Treatment with FGF-23 in combination with an ERK1/2 inhibitor significantly increased VSMC calcification.

Increasing interest is focusing on the role of the FGF-23/Klotho axis in mediating vascular calcification. However, the underpinning mechanisms have yet to be fully elucidated. Murine VSMCs were cultured in calcifying medium for a 21 d period. FGF-23 mRNA expression was significantly up-regulated by 7 d (1.63-fold; P < 0.001), with a concomitant increase in protein expression. mRNA and protein expression of both FGFR1 and Klotho were confirmed. Increased FGF-23 and Klotho protein expression was also observed in the calcified media of Enpp1−/− mouse aortic tissue. Reduced calcium deposition was observed in calcifying VSMCs cultured with recombinant FGF-23 (10 ng/ml; 28.1% decrease; P < 0.01). Calcifying VSMCs treated with PD173074, an inhibitor of FGFR1 and FGFR3, showed significantly increased calcification (50 nM; 87.8% increase; P < 0.001). FGF-23 exposure induced phosphorylation of ERK1/2. Treatment with FGF-23 in combination with PD98059, an ERK1/2 inhibitor, significantly increased VSMC calcification (10 μM; 41.3% increase; P < 0.01). Use of FGF-23 may represent a novel therapeutic strategy for inhibiting vascular calcification.