Imatinib has minimal effects on inflammatory and osteopenic phenotypes in a murine cherubism model
Imatinib has minimal effects on inflammatory and osteopenic phenotypes in a murine cherubism model
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DOI：
10.1111/odi.14073
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发表时间：
2021-11-23
期刊：
影响因子：
3.8
通讯作者：
Morita, Yoshitaka
中科院分区：
文献类型：
--
作者：
Mukai, Tomoyuki;Akagi, Takahiko;Morita, Yoshitaka
目的巨颌症是一种以双侧颌骨畸形为特征的遗传性疾病。相关的颌骨病变在青春期后消退，而严重的病例需要手术治疗。虽然已经测试了几种药物，但尚未建立针对巨像症的基本治疗策略。伊马替尼的有效性最近有报道，但其药物机制仍不清楚。在这项研究中，我们测试了伊马替尼的影响使用cherubism小鼠模型。方法我们使用Sh 3bp 2 P416 R巨像突变小鼠，表现出全身器官炎症和骨量减少。使用原代骨髓源性巨噬细胞测定伊马替尼的作用。伊马替尼腹腔注射给药的小鼠，血清肿瘤坏死因子-α（TNF α），器官炎症和骨特性进行了检查。结果与野生型巨噬细胞相比，巨噬细胞巨胖突变体在对脂多糖的反应中产生更高水平的TNF α，伊马替尼没有显著抑制TNF α的产生。尽管伊马替尼在体外抑制破骨细胞的形成，但在体内给药并不能抑制器官炎症和骨质减少。结论伊马替尼体内给药对巨像症突变小鼠的治疗作用最小。为了建立更好的药物干预措施，有必要将小鼠模型的新发现与确诊为巨像症患者的临床数据相结合。
Objective Cherubism is a genetic disorder characterised by bilateral jawbone deformation. The associated jawbone lesions regress after puberty, whereas severe cases require surgical treatment. Although several drugs have been tested, fundamental treatment strategies for cherubism have not been established. The effectiveness of imatinib has recently been reported; however, its pharmaceutical mechanism remains unclear. In this study, we tested the effects of imatinib using a cherubism mouse model. Methods We used Sh3bp2 P416R cherubism mutant mice, which exhibit systemic organ inflammation and osteopenia. The effects of imatinib were determined using primary bone marrow-derived macrophages. Imatinib was administered intraperitoneally to the mice, and serum tumour necrosis factor-alpha (TNF alpha), organ inflammation and bone properties were examined. Results The cherubism mutant macrophages produced higher levels of TNF alpha in response to lipopolysaccharide compared to wild-type macrophages, and imatinib did not significantly suppress TNF alpha production. Although imatinib suppressed osteoclast formation in vitro, administering it in vivo did not suppress organ inflammation and osteopenia. Conclusion The in vivo administration of imatinib had a minimal therapeutic impact in cherubism mutant mice. To establish better pharmaceutical interventions, it is necessary to integrate new findings from murine models with clinical data from patients with a definitive diagnosis of cherubism.