Second-Generation SYK Inhibitor Entospletinib Ameliorates Fully Established Inflammation and Bone Destruction in the Cherubism Mouse Model.
Second-Generation SYK Inhibitor Entospletinib Ameliorates Fully Established Inflammation and Bone Destruction in the Cherubism Mouse Model.
复制标题
第二代 SYK 抑制剂 Entospletinib 可改善 Cherubism 小鼠模型中完全建立的炎症和骨破坏。
DOI：
10.1002/jbmr.3449
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发表时间：
2018
期刊：
影响因子：
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通讯作者：
Ueki,Yasuyoshi
中科院分区：
文献类型：
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作者：
Yoshimoto,Tetsuya;Hayashi,Tatsuhide;Kondo,Toshio;Kittaka,Mizuho;Reichenberger,ErnstJ;Ueki,Yasuyoshi
切尔鲁比氏症是一种以上颌骨和下颌骨破坏为特征的颅面部疾病。SH3结构域结合蛋白2(SH3BP2)的功能获得突变是纤维性炎性病变引起的过度骨吸收的原因。一种纯合子敲入(Ki)小鼠模型(Sh3bp2KI/Ki)发生自体炎症，导致全身性骨破坏。尽管对新生儿Sh3bp2KI/KImice给予肿瘤坏死因子-α阻滞剂依那西普预防了疾病的发生，但这种治疗对成年Sh3bp2KI/KImice或已有损害的人类小天使症患者无效。由于基因切除髓系细胞中的脾酪氨酸激酶(SYK)使Sh3bp2KI/KImice免于炎症，我们研究了应用SYK抑制剂是否能改善成年Sh3bp2KI/KImice的完全发展的天使症症状。10周龄Sh3bp2KI/KImice每日腹腔注射Entospletinib(GS-9973)，连续6周。GS-9973治疗改善了面部肿胀，肺和肝组织的组织形态计量学分析表明，GS-9973治疗显著减少了与血清肿瘤坏死因子-α水平相关的炎性浸润物。微电脑断层扫描(μCT)分析显示，与二甲基亚砜治疗的Sh3bp2KI/KImice相比，GS-9973治疗减轻了Sh3bp2KI/KImice的下颌骨、颅骨、踝关节和肘关节的骨侵蚀。综上所述，这些结果表明，给予SYK抑制剂可以改善小鼠中已经确立的天使症表型，这表明药物抑制SYK可能是疾病进展活跃的天使症患者的一种治疗选择。2018年美国骨与矿物研究学会。
Cherubism is a craniofacial disorder characterized by maxillary and mandibular bone destruction. Gain‐of‐function mutations in the SH3‐domain binding protein 2 (SH3BP2) are responsible for the excessive bone resorption caused by fibrous inflammatory lesions. A homozygous knock‐in (KI) mouse model for cherubism (Sh3bp2KI/KI) develops autoinflammation resulting in systemic bone destruction. Although administration of the TNF‐α blocker etanercept to neonatalSh3bp2KI/KImice prevented the disease onset, this therapy was not effective for adultSh3bp2KI/KImice or human cherubism patients who already had lesions. Because genetic ablation of spleen tyrosine kinase (SYK) in myeloid cells rescuesSh3bp2KI/KImice from inflammation, we examined whether SYK inhibitor administration can improve fully developed cherubism symptoms in adultSh3bp2KI/KImice. Entospletinib (GS‐9973) was intraperitoneally injected into 10‐week‐oldSh3bp2KI/KImice every day for 6 weeks. Treatment with GS‐9973 improved facial swelling and histomorphometric analysis of lung and liver tissue showed that GS‐9973 administration significantly reduced inflammatory infiltrates associated with decreased levels of serum TNF‐α. Micro–computed tomography (μCT) analysis showed that GS‐9973 treatment reduced bone erosion in mandibles, calvariae, and ankle and elbow joints ofSh3bp2KI/KImice compared toSh3bp2KI/KImice treated with dimethyl sulfoxide (DMSO). Taken together, the results demonstrate that administration of the SYK inhibitor ameliorates an already established cherubism phenotype in mice, suggesting that pharmacological inhibition of SYK may be a treatment option for cherubism patients with active disease progression. © 2018 American Society for Bone and Mineral Research.