Inhibition of the ATG4-LC3 pathway suppressed osteoclast maturation
Inhibition of the ATG4-LC3 pathway suppressed osteoclast maturation
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DOI：
10.1016/j.bbrc.2022.09.065
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发表时间：
2022-10-02
影响因子：
3.1
通讯作者：
Jimi，Eijiro
中科院分区：
文献类型：
--
作者：
Hiura，Fumitaka;Kawabata，Yuko;Jimi，Eijiro
自噬是一种非选择性的行为，即细胞降解自身的一部分，重新利用降解的细胞成分。在自噬相关基因(ATG)家族成员中，ATG4蛋白在微管相关蛋白1轻链3(LC3)磷脂酰乙醇胺(PE)系统中起着至关重要的作用，该系统是自噬小体成熟所必需的。虽然自噬已被证明与破骨细胞性骨吸收有关，但ATG4/LC3在骨吸收中的作用尚不清楚。当小鼠骨髓细胞在加入巨噬细胞集落刺激因子(M-κ)后1h加入不同浓度的ATG4B特异性抑制剂NSC185058(NSC)后，NSC可抑制破骨细胞的生成，且呈剂量依赖关系。在破骨细胞分化的后期加入NSC可抑制多核，并减少成熟破骨细胞标志物ASDC-STAMP、MMP9和Ctsk的表达。NSC还抑制成熟破骨细胞肌动蛋白环的形成和凹坑的形成。8周龄雄性小鼠右侧上颌第二磨牙丝线结扎建立牙周炎模型，注射NSC或不注射NSC均可抑制牙槽骨吸收，使破骨细胞数量减少。这些结果表明，Lc3对破骨细胞的成熟具有重要作用，抑制Lc3是治疗牙周病的一种新策略。
Autophagy is a non-selective action in which cells degrade parts of themselves, reusing degraded cellular components. Among autophagy-related gene (ATG) family members, ATG4 proteins play crucial roles in the microtubule-associated protein 1 light chain 3 (LC3) phosphatidylethanolamine (PE) system which is essential for autophagosome maturation. Although autophagy has been shown to be involved in osteoclastic bone resorption, the role of ATG4/LC3 in bone resorption remains unclear. When mouse bone marrow cells were treated with various concentrations of NSC185058 (NSC), a specific inhibitor of ATG4B, 1 h prior to treatment with receptor activator of NF-κB ligand (RANKL) in the presence of macrophage colony stimulating factor (M-CSF), NSC inhibited osteoclastogenesis in a dose-dependent manner. Addition of NSC in the late stages of osteoclast differentiation suppressed multinucleation and reduced the expression of markers for mature osteoclasts such asDc-stamp, Mmp9,andCtsk. NSC also suppressed actin ring formation and pit formation in mature osteoclasts. When a periodontitis model involving eight-week-old male mice in which the right maxillary second molar had been ligated with silk thread was injected with or without NSC, alveolar bone resorption was suppressed by a decrease in the number of osteoclasts in the NSC-treated group. These results suggest that LC3 is important for the maturation of osteoclasts and that LC3 inhibition is a new therapeutic strategy for periodontal disease.