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缺氧条件下 A20 通过 TRAF6 依赖性自噬抑制人牙周膜细胞破骨细胞生成。

A20 inhibits osteoclastogenesis via TRAF6-dependent autophagy in human periodontal ligament cells under hypoxia.

机构信息

Jiangsu Key Laboratory of Oral Diseases, Nanjing Medical University, Nanjing, China.

Department of Periodontics, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China.

出版信息

Cell Prolif. 2020 Mar;53(3):e12778. doi: 10.1111/cpr.12778. Epub 2020 Feb 6.

DOI:10.1111/cpr.12778
PMID:32027437
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC7106956/
Abstract

OBJECTIVES

A20 exerts an anti-osteoclastogenic effect through the inhibition of NF-κB signalling in periodontitis. It also regulates autophagy via ubiquitin modification. This study was aimed at exploring the relationship between A20 and autophagy in anti-osteoclastogenesis in human periodontal ligament cells (hPDLCs) under hypoxia.

MATERIALS AND METHODS

Real-time PCR and Western blot were used to detect relative mRNA and protein levels. The formation of autophagosomes was measured by TEM. Osteoclastic differentiation was assessed by TRAP staining and hydroxyapatite resorption assay. The interactions between different proteins were observed by co-IP.

RESULTS

Cells cultured under 2% O₂ exhibited decreased A20 expression and increased RANKL/OPG (R/O) ratio. There was a negative correlation between A20 and TRAF6, and similar results were found with autophagic flux. A20 delayed the increase in R/O ratio under hypoxia. Autophagy in hPDLCs and osteoclast differentiation and hydroxyapatite resorption areas in mouse bone marrow mononuclear cells (BMMCs) were inhibited by A20. Moreover, inhibition of autophagy using 3-MA resulted in increased expression of A20 and decreased number and function of osteoclasts. In addition, A20 inhibited polyubiquitination at K63 and enhanced that at K48 in TRAF6 to suppress autophagy under hypoxic conditions.

CONCLUSIONS

A20 inhibits osteoclastogenesis via inhibition of TRAF6-dependent autophagy in hPDLCs under hypoxia. These findings suggest that A20 may be a key gene target during bone loss in periodontitis via TRAF6-mediated inhibition of autophagy.

摘要

目的

A20 通过抑制 NF-κB 信号通路在牙周炎中发挥抗破骨细胞生成作用。它还通过泛素修饰来调节自噬。本研究旨在探讨缺氧下人牙周膜细胞（hPDLC）中 A20 与自噬在抗破骨细胞生成中的关系。

材料和方法

实时 PCR 和 Western blot 用于检测相对 mRNA 和蛋白水平。TEM 测量自噬体的形成。TRAP 染色和羟磷灰石吸收试验评估破骨细胞分化。通过 co-IP 观察不同蛋白之间的相互作用。

结果

在 2%O₂ 下培养的细胞显示 A20 表达降低和 RANKL/OPG（R/O）比值增加。A20 与 TRAF6 呈负相关，自噬流也有类似结果。A20 延迟了缺氧下 R/O 比值的增加。A20 抑制 hPDLC 中的自噬和破骨细胞分化以及小鼠骨髓单核细胞（BMMC）中的羟磷灰石吸收面积。此外，使用 3-MA 抑制自噬会导致 A20 表达增加，破骨细胞数量和功能减少。此外，A20 在缺氧条件下抑制 TRAF6 依赖性泛素化，抑制 K63 多泛素化，增强 K48 多泛素化，从而抑制自噬。

结论

A20 通过抑制缺氧下人牙周膜细胞中 TRAF6 依赖性自噬来抑制破骨细胞生成。这些发现表明，A20 可能通过 TRAF6 介导的自噬抑制成为牙周炎骨丢失过程中的关键基因靶标。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4163/7106956/ac0c4341885f/CPR-53-e12778-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4163/7106956/1254657468ab/CPR-53-e12778-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4163/7106956/b4423bf19887/CPR-53-e12778-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4163/7106956/313a8b554f15/CPR-53-e12778-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4163/7106956/5ac65b4162be/CPR-53-e12778-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4163/7106956/0c0f69914a8b/CPR-53-e12778-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4163/7106956/3fcadd9d525c/CPR-53-e12778-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4163/7106956/ac0c4341885f/CPR-53-e12778-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4163/7106956/1254657468ab/CPR-53-e12778-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4163/7106956/b4423bf19887/CPR-53-e12778-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4163/7106956/313a8b554f15/CPR-53-e12778-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4163/7106956/5ac65b4162be/CPR-53-e12778-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4163/7106956/0c0f69914a8b/CPR-53-e12778-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4163/7106956/3fcadd9d525c/CPR-53-e12778-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/4163/7106956/ac0c4341885f/CPR-53-e12778-g007.jpg

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