Fibroblast growth factor-23 remodels vascular extracellular matrix via glycosaminoglycan induction: implications for calcification in chronic kidney disease

Chronic kidney disease (CKD) leads to accumulation of uremic toxins, which contribute to cardiovascular disease (CVD) and mortality. Among these, fibroblast growth factor 23 (FGF-23), a bone-derived hormone, is associated with arterial stiffness, vascular calcification, and left ventricular hypertrophy. However, the mechanisms linking elevated FGF-23 levels to vascular alterations remain poorly understood. We hypothesized that FGF-23 modulates the expression of sulfated glycosaminoglycans (sGAGs) and hyaluronic acid (HA) in vascular cells. Rat vascular smooth muscle cells (VSMCs) and human endothelial cells (ECs) were treated with FGF-23 ± its co-receptor Klotho and analyzed using qPCR, Western blotting, Blyscan assay, Alcian blue staining, ELISA, and reporter assays. FGF-23 significantly increased sGAG (2.5-fold) and HA (1.6-fold) levels in VSMCs, and sGAG (50-fold) and HA (3.7-fold) levels in ECs. Klotho alone induced a ∼72-fold rise in sGAGs in ECs but had no effect in VSMCs. FGF-23 also upregulated GAG-specific gene expressions of carbohydrate sulfotransferase 1 and xylosyltransferase 2 ∼1.6-fold and increased HA-specific hyaluronan synthase-2 and -3 protein expression. These effects were mediated by ERK and NF-κB signaling. To evaluate biological relevance, we assessed calcium- and phosphate-induced calcification in VSMCs. FGF-23 significantly enhanced calcification by ∼65%, which paralleled elevated sGAG levels. Inhibition of GAG sulfation with NaClO₃ significantly reduced sGAGs and prevented FGF-23-induced calcification. Similarly, the FGFR inhibitor AZD4547 abolished FGF-23-induced increases in sGAGs and calcification in both VSMCs and ECs. These findings indicate that FGF-23 modulates vascular GAG composition and promotes calcification, thereby contributing to pathological vascular remodeling in CKD.