Xiao Liping, He Wei, Hurley Marja M
Division of Endocrinology and Metabolism, Department of Medicine, UConn Health School of Medicine, Farmington, CT, 06030, USA.
Sci Rep. 2025 Mar 28;15(1):10727. doi: 10.1038/s41598-025-95335-w.
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.
在人源化镰状细胞病（SCD）小鼠的血清中，成纤维细胞生长因子23（FGF23）水平升高。由于FGF23与骨形成受损有关，我们研究了FGF23中和抗体（FGF23Ab）对SCD小鼠骨质流失的影响。将健康对照（Ctrl）小鼠和5月龄的雌性SCD小鼠用FGF23Ab或同型特异性IgG处理6周。FGF23Ab使SCD小鼠显著降低的血细胞比容有所升高。SCD小鼠股骨的显微CT显示，与Ctrl小鼠相比，干骺端骨体积/总体积没有显著降低。然而，SCD小鼠股骨的组织形态计量学显示，矿化沉积率、骨形成率、标记间厚度和类骨质表面显著降低，而FGF23Ab可使其升高。FGF23Ab降低了SCD小鼠中显著增加的破骨细胞数量/骨周长。在成骨培养基中培养的骨髓基质细胞（BMSC）显示，SCD-IgG-BMSC中矿化结节显著减少，而在SCD-FGF23Ab-BMSC中增加。FGF23和αKlotho蛋白在SCD-IgG-BMSC中显著增加，且未被FGF23Ab降低。然而，FGF23发出信号所通过的受体——磷酸化FGF受体-1被FGF23Ab显著降低。矿化抑制剂骨桥蛋白在SCD-IgG-BMSC培养物中显著增加，而被FGF23Ab降低。我们得出结论，FGF23Ab可能有效改善雌性SCD小鼠骨形成减少的一些参数。
