The Inducible Nitric Oxide Synthase Pathway Promotes Osteoclastogenesis under Hypoxic Culture Conditions
The Inducible Nitric Oxide Synthase Pathway Promotes Osteoclastogenesis under Hypoxic Culture Conditions
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DOI：
10.1016/j.ajpath.2021.08.014
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发表时间：
2021-11-19
影响因子：
6
通讯作者：
Aoyama, Mineyoshi
中科院分区：
文献类型：
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作者：
Kondo, Takao;Otsuka, Yuto;Aoyama, Mineyoshi
骨稳态依赖于破骨细胞(OCs)的骨吸收和成骨细胞的骨形成之间的平衡。在包括类风湿性关节炎在内的各种病理条件下，骨吸收会变得过度。以往的研究表明，在低氧条件下，OC的形成被促进。然而，在低氧条件下OC形成的确切机制尚未阐明。本研究探讨了诱导型一氧化氮合酶(INOS)在低氧条件下OC分化中的作用。取小鼠原代骨髓细胞，用核因子-kB受体激活剂和巨噬细胞集落刺激因子刺激其向OC分化。低氧(氧浓度，5%)条件下培养的OCs数量较常氧(氧浓度，20%)条件下培养的OCs数量增加。低氧条件下，iNOS基因和蛋白表达增加。在低氧条件下添加iNOS抑制剂可抑制破骨细胞的生成。在常氧培养中加入一氧化氮供体可促进破骨细胞的形成。此外，在iNOS抑制实验和一氧化氮供体实验中，胰岛素样生长因子2的表达都发生了显著变化。这些数据可能为在包括类风湿性关节炎在内的几种缺氧病理条件下过度破骨细胞生成的治疗提供线索。(Am J Pathol2021年，191.2072年-2079年；https://doi.org/10.1016/j.ajpath.2021.08.014)
Bone homeostasis depends on the balance between bone resorption by osteoclasts (OCs) and bone formation by osteoblasts. Bone resorption can become excessive under various pathologic conditions, including rheumatoid arthritis. Previous studies have shown that OC formation is promoted under hypoxia. However, the precise mechanisms behind OC formation under hypoxia have not been elucidated. The present study investigated the role of inducible nitric oxide synthase (iNOS) in OC differentiation under hypoxia. Primary bone marrow cells obtained from mice were stimulated with receptor activator of NF-KB ligand and macrophage colony-stimulating factor to induce OC differentiation. The number of OCs increased in culture under hypoxia (oxygen concentration, 5%) compared with that under normoxia (oxygen concentration, 20%). iNOS gene and protein expression increased in culture under hypoxia. Addition of an iNOS inhibitor under hypoxic conditions suppressed osteoclastogenesis. Addition of a nitric oxide donor to the normoxic culture promoted osteoclastogenesis. Furthermore, insulin-like growth factor 2 expression was significantly altered in both iNOS inhibition experiments and nitric oxide donor experiments. These data might provide clues to therapies for excessive osteoclastogenesis under several hypoxic pathologic conditions, including rheumatoid arthritis. (Am J Pathol 2021, 191: 2072-2079; https://doi.org/10.1016/j.ajpath.2021.08.014)