Fibroblast growth factor 23 neutralizing antibody partially rescues bone loss and increases hematocrit in sickle cell disease mice
Abstract
Fibroblast Growth Factor 23 (FGF23) is increased in serum of humanized Sickle Cell Disease (SCD) mice. Since FGF23 is associated with impaired bone formation, we examined the effect of FGF23-neutralizing antibody (FGF23Ab) on bone loss in SCD mice. Healthy control (Ctrl) and SCD 5-months-old female mice were treated with FGF23Ab or isotype-specific IgG for 6 weeks. Significantly reduced hematocrit in SCD mice was increased by FGF23Ab. MicroCT of SCD femurs revealed no significant reduction in metaphyseal bone volume/total volume vs. Ctrl mice. However, histomorphometry of SCD femur revealed significantly reduced mineral apposition rate, bone formation rate, inter-label thickness, and osteoid surface, which were increased by FGF23Ab. Significantly increased osteoclast number/bone perimeter in SCD mice was reduced by FGF23Ab. Bone marrow stromal cells (BMSC) cultured in osteogenic media revealed significantly reduced mineralized nodules in SCD-IgG-BMSC that was increased in SCD-FGF23Ab-BMSC. FGF23 and αKlotho protein was significantly increased in SCD-IgG-BMSC and was not reduced by FGF23Ab. However, phosphorylated FGF Receptor-1, the receptor through which FGF23 signals, was significantly reduced by FGF23Ab. The mineralization inhibitor osteopontin was significantly increased in SCD-IgG-BMSC cultures and was reduced by FGF23Ab. We conclude that FGF23Ab may be efficacious in improving some parameters of reduced bone formation in female SCD mice.
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