Tripathi Ashish Kumar, Dabeer Sadaf, Song Jun, Vikulina Tatyana, Roser-Page Susanne, Alvarez Jessica A, Archer David R, Weitzmann M Neale
Division of Endocrinology, Metabolism, and Lipids, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia, USA.
The Atlanta Department of Veterans Affairs Medical Center, Decatur, GA, USA.
Cell Death Dis. 2024 Dec 18;15(12):907. doi: 10.1038/s41419-024-07296-z.
Sickle cell disease (SCD) is a severe hematological disorder characterized by erythrocyte sickling that causes significant morbidity and mortality. Skeletal complications of SCD include a high incidence of bone loss, especially in vertebrae, leading to fragility fractures that contribute to disease burden. Whether hydroxyurea (HU), a front-line therapy for SCD ameliorates bone disease has not been established. To investigate HU action on SCD-related vertebral defects, we used HU-treated "Townes" mice, an SCD animal model and performed high-resolution micro-computed tomography (µCT) imaging to resolve bone volume and micro-architectural structure of cortical and trabecular bone, the two major compartments contributing to bone mass and strength. Our data revealed that cortical bone was significantly diminished in the vertebrae of skeletally mature (representing adults) and immature (representing children) SCD mice, while only mature mice lost trabecular bone mass. Administration of HU ameliorated cortical bone loss in mature SCD mice, but paradoxically promoted trabecular bone decline in both groups. We further investigated the mechanisms of HU action in wild-type C57BL6/J mice. HU caused dose-dependent trabecular bone loss due to diminished osteoclast and osteoblast function, indicative of a low bone turnover state. Mechanistic investigations in vitro revealed that HU impeded osteoblast-progenitor proliferation and early differentiation, and diminished osteoclastogenic cytokine production, blunting osteoclast formation as well as the activity of mature osteoclasts. HU further, suppressed mitochondrial, but not glycolytic energy metabolism in both differentiating osteoblasts and differentiated osteoclasts. Collectively, these findings reveal that despite ameliorating cortical bone loss, HU inhibits trabecular bone formation and resorption, by suppressing mitochondrial energy metabolism and blunting the differentiation and/or activity of osteoblasts and osteoclasts. Together HU drives a low bone turnover state culminating in trabecular bone loss. Further investigation into HU's impact on bone in SCD patients is warranted for understanding and managing skeletal complications in this population.
镰状细胞病（SCD）是一种严重的血液系统疾病，其特征是红细胞镰变，可导致显著的发病率和死亡率。SCD的骨骼并发症包括骨质流失发生率高，尤其是在椎骨中，导致脆性骨折，增加了疾病负担。作为SCD一线治疗药物的羟基脲（HU）是否能改善骨病尚未明确。为了研究HU对SCD相关椎体缺陷的作用，我们使用了HU治疗的“SCD动物模型“Townes”小鼠，并进行了高分辨率微计算机断层扫描（µCT）成像，以解析皮质骨和小梁骨的骨体积和微结构，这两个主要部分共同构成了骨质量和强度。我们的数据显示，在骨骼成熟（代表成年人）和未成熟（代表儿童）的SCD小鼠的椎骨中，皮质骨显著减少，而只有成熟小鼠的小梁骨量减少。给予HU可改善成熟SCD小鼠的皮质骨流失，但矛盾的是，两组小鼠的小梁骨量均下降。我们进一步研究了HU在野生型C57BL6/J小鼠中的作用机制。由于破骨细胞和成骨细胞功能减弱，HU导致剂量依赖性小梁骨流失，表明骨转换率低。体外机制研究表明，HU阻碍成骨祖细胞增殖和早期分化，并减少破骨细胞生成细胞因子的产生，抑制破骨细胞形成以及成熟破骨细胞的活性。此外，HU抑制分化中的成骨细胞和分化后的破骨细胞的线粒体能量代谢，但不抑制糖酵解能量代谢。总的来说，这些发现表明，尽管HU改善了皮质骨流失，但它通过抑制线粒体能量代谢以及成骨细胞和破骨细胞的分化和/或活性，抑制了小梁骨的形成和吸收。HU共同导致低骨转换状态，最终导致小梁骨流失。有必要进一步研究HU对SCD患者骨骼的影响，以了解和管理该人群的骨骼并发症。
