The multi‐kinase inhibitor dasatinib suppresses autoinflammation and increases bone density in a mouse model for chronic recurrent multifocal osteomyelitis
The multi‐kinase inhibitor dasatinib suppresses autoinflammation and increases bone density in a mouse model for chronic recurrent multifocal osteomyelitis
复制标题
多激酶抑制剂达沙替尼可抑制慢性复发性多灶性骨髓炎小鼠模型的自身炎症并增加骨密度
DOI：
10.1002/cbf.3617
复制
发表时间：
2021
影响因子：
3.6
通讯作者：
Abe Koichiro
中科院分区：
文献类型：
--
作者：
Yoshikawa Ryo;Abe Koichiro
慢性复发性多灶性骨髓炎（CRMO）是一种自身炎症性骨病，表现为骨破坏和疼痛。尽管遗传学研究已经确定了涉及CRMO的信号通路，但分子靶向药物仍然不可用。我们使用CRMO动物模型作为候选治疗剂的体内筛选系统。Src家族激酶（SFKs）成员之一的功能增益突变inFgr可导致ali18小鼠外周足部炎症和骨密度（BMD）降低。选择SFK抑制剂达沙替尼每天给ali18只小鼠，持续2周。局部炎症和骨密度分别通过临床评分和计算机断层扫描进行评估。在少量动物中进行的初步研究表明，达沙替尼有效地抑制了ali18小鼠的早期自身炎症。连续灌胃达沙替尼对一组ali18小鼠证实了对足跖肿胀的显著抑制，无副作用。组织学分析显示，给予达沙替尼的动物，异常增殖的骨髓细胞和炎症浸润到患处的皮肤明显减少。此外，ali18长骨的骨小梁骨密度恢复到与野生型小鼠相似的水平。我们的研究结果表明，在CRMO模型动物中，达沙替尼激酶抑制剂完全抑制了自身炎症和相关的骨表型。因此，强烈建议达沙替尼可结合FGR位点的分子诊断用于CRMO的临床治疗。研究意义在CRMO模型动物中，激酶抑制剂达沙替尼能有效抑制自身炎症和相关骨表型。结合FGR位点的分子分析，达沙替尼是临床治疗CRMO的有力候选药物。我们建议本研究采用的动物模型可用于筛选该药物和其他潜在的CRMO药物。
Chronic recurrent multifocal osteomyelitis (CRMO) is an autoinflammatory bone disease that presents with bone destruction and pain. Although genetic studies have identified signalling pathways involving CRMO, molecularly targeted drugs remain unavailable. We used an animal model of CRMO as an in vivo screening system for candidate therapeutic agents. A gain‐of‐function mutation inFgr, a member of Src family kinases (SFKs), causes peripheral paw inflammation and reduced bone mineral density (BMD) inAli18mice. The SFK inhibitor dasatinib was selected for administration toAli18mice daily for 2 weeks. Local inflammation and BMD were assessed by clinical scoring and computed tomography, respectively. Pilot studies in a small number of animals showed that dasatinib administration effectively suppressed the early phase of autoinflammation inAli18mice. Serial oral gavage of dasatinib to a group ofAli18mice confirmed significant suppression of paw swelling with no side effects. Histological analysis revealed that abnormal proliferative bone marrow cells and inflammatory infiltration into the skin in the affected area were clearly reduced in the animals with dasatinib administration. Further, trabecular BMD inAli18long bones was restored to levels similar to that found in wild type mice. Our results indicate that autoinflammation and related‐bone phenotypes were completely suppressed by the dasatinib kinase inhibitor in CRMO model animals. Thus, it is strongly suggested that dasatinib can be used for clinical treatments of CRMO with the combination of molecular diagnosis of the FGR locus.Significance of the studyAutoinflammation and related‐bone phenotypes were effectively suppressed by the kinase inhibitor dasatinib in CRMO model animals. In combination with molecular analysis of the FGR locus, dasatinib is a strong candidate for the clinical treatments of CRMO. We propose that the animal model employed in this study can be used to screen this and other potential drugs for CRMO.
登录
查看更多内容
影响因子：
3.9
作者：
Schnabel, Anja;Range, Ursula;Hedrich, Christian M.
通讯作者：
Hedrich, Christian M.
治疗浓度的达沙替尼抑制体外破骨细胞生成
影响因子：
11.4
作者：
K. Vandyke;A. Dewar;A. Farrugia;S. Fitter;L. To;T. Hughes;A. Zannettino
通讯作者：
A. Zannettino
影响因子：
8
作者：
Lee, Y-C;Huang, C-F;Murshed, M.;Chu, K.;Araujo, J. C.;Ye, X.;deCrombrugghe, B.;Yu-Lee, L-Y;Gallick, G. E.;Lin, S-H
通讯作者：
Lin, S-H
影响因子：
4
作者：
Weir MC;Shu ST;Patel RK;Hellwig S;Chen L;Tan L;Gray NS;Smithgall TE
通讯作者：
Smithgall TE
影响因子：
158.5
作者：
Talpaz, Moshe;Shah, Neil P.;Sawyers, Charles L.
通讯作者：
Sawyers, Charles L.