Division of Endocrinology and Metabolism, Department of Medicine, UConn Health School of Medicine, Farmington, CT, 06030, USA.
Sci Rep. 2024 Sep 27;14(1):22330. doi: 10.1038/s41598-024-69589-9.
We assessed the effect of GBT1118, a sickle hemoglobin polymerization inhibitor on bone loss in humanized sickle cell disease (SCD) mice. Healthy control (Ctrl) 4-months-old female and male mice were fed Vehicle-chow for 2-months, while SCD mice were fed Vehicle-chow or GBT1118-chow. By micro-CT, GBT1118 significantly increased femur metaphyseal trabecular thickness (Tb.Th) and tissue mineral density (TMD), and significantly decreased trabecular spacing in female SCD mice. In SCD male mice, there was significant reduction in epiphyseal trabecular bone volume fraction (BV/TV), Tb.Th and TMD and GBT1118 significantly increased BV/TV and TMD but not Tb.Th. A significant decrease in cortical area fraction in SCD female mice was rescued by GBT1118 but not SCD males. Markedly decreased mineralized femur trabeculae in SCD females and males was partially rescued by GBT1118. Bone histomorphometry of femurs demonstrated significantly decreased bone formation parameters and increased bone resorption parameters in SCD mice of both sex that were rescued by GBT1118. Significant alteration in bone and hypoxia related genes of SCD mice of both sexes were differentially modulated by GBT1118. We conclude that "a sickle hemoglobin polymerization inhibitor" might be efficacious in improving some parameters of SCD bone loss.
我们评估了 GBT1118（一种镰状血红蛋白聚合抑制剂）对人源化镰状细胞病（SCD）小鼠骨丢失的影响。健康对照组（Ctrl）4 月龄雌性和雄性小鼠喂食 Vehicle 饲料 2 个月，而 SCD 小鼠喂食 Vehicle 饲料或 GBT1118 饲料。通过 micro-CT，GBT1118 显著增加了雌性 SCD 小鼠股骨骺端的骨小梁厚度（Tb.Th）和组织矿密度（TMD），并显著减少了骨小梁间距。在 SCD 雄性小鼠中，骺端骨小梁骨体积分数（BV/TV）、Tb.Th 和 TMD 显著降低，GBT1118 显著增加了 BV/TV 和 TMD，但未增加 Tb.Th。GBT1118 可挽救 SCD 雌性小鼠皮质面积分数的显著降低，但对 SCD 雄性小鼠无影响。GBT1118 部分挽救了 SCD 雌性和雄性小鼠矿化股骨小梁的明显减少。股骨的骨组织形态计量学显示，SCD 雌雄小鼠的骨形成参数显著降低，骨吸收参数显著增加，而 GBT1118 可挽救这些参数。GBT1118 对 SCD 雌雄小鼠的骨和缺氧相关基因的显著改变进行了差异调节。我们得出结论，“一种镰状血红蛋白聚合抑制剂”可能对改善 SCD 骨丢失的某些参数有效。
