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自噬 LC3 钙化细胞外囊泡引发骨关节炎软骨钙化。

Autophagic LC3 calcified extracellular vesicles initiate cartilage calcification in osteoarthritis.

机构信息

State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Key Laboratory of Stomatology, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, China.

State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi International Joint Research Center for Oral Diseases, Center for Tissue Engineering, School of Stomatology, The Fourth Military Medical University, Xi'an, Shaanxi, China.

出版信息

Sci Adv. 2022 May 13;8(19):eabn1556. doi: 10.1126/sciadv.abn1556. Epub 2022 May 11.

DOI:10.1126/sciadv.abn1556
PMID:35544558
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9094669/
Abstract

Pathological cartilage calcification plays an important role in osteoarthritis progression but in which the origin of calcified extracellular vesicles (EVs) and their effects remain unknown. Here, we demonstrate that pathological cartilage calcification occurs in the early stage of the osteoarthritis in which the calcified EVs are closely involved. Autophagosomes carrying the minerals are released in EVs, and calcification is induced by those autophagy-regulated calcified EVs. Autophagy-derived microtubule-associated proteins 1A/1B light chain 3B (LC3)-positive EVs are the major population of calcified EVs that initiate pathological calcification. Release of LC3-positive calcified EVs is caused by blockage of the autophagy flux resulted from histone deacetylase 6 (HDAC6)-mediated microtubule destabilization. Inhibition of HDAC6 activity blocks the release of the LC3-positive calcified EVs by chondrocytes and effectively reverses the pathological calcification and degradation of cartilage. The present work discovers that calcified EVs derived from autophagosomes initiate pathological cartilage calcification in osteoarthritis, with potential therapeutic targeting implication.

摘要

病理性软骨钙化在骨关节炎的进展中起着重要作用，但钙化细胞外囊泡（EVs）的起源及其作用仍不清楚。在这里，我们证明了病理性软骨钙化发生在骨关节炎的早期阶段，其中钙化 EVs 密切参与其中。携带矿物质的自噬体在 EVs 中释放，并且那些受自噬调节的钙化 EVs 诱导钙化。自噬衍生的微管相关蛋白 1A/1B 轻链 3B（LC3）阳性 EVs 是引发病理性钙化的主要钙化 EVs 群体。LC3 阳性钙化 EVs 的释放是由于组蛋白去乙酰化酶 6（HDAC6）介导的微管去稳定化导致自噬通量受阻引起的。抑制 HDAC6 活性可阻止软骨细胞释放 LC3 阳性钙化 EVs，并有效逆转病理性钙化和软骨降解。本研究发现，自噬体衍生的钙化 EVs 引发骨关节炎中的病理性软骨钙化，具有潜在的治疗靶向意义。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2a6c/9094669/4d19d7d69b29/sciadv.abn1556-f9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2a6c/9094669/2a6b1a5142b7/sciadv.abn1556-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2a6c/9094669/bbad082d823d/sciadv.abn1556-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2a6c/9094669/b1cd58909ab4/sciadv.abn1556-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2a6c/9094669/e4dd09ed4a98/sciadv.abn1556-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2a6c/9094669/5edf0410e4d5/sciadv.abn1556-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2a6c/9094669/d2ac8c41d195/sciadv.abn1556-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2a6c/9094669/0e441e8128c0/sciadv.abn1556-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2a6c/9094669/97d7dcc28116/sciadv.abn1556-f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2a6c/9094669/4d19d7d69b29/sciadv.abn1556-f9.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2a6c/9094669/2a6b1a5142b7/sciadv.abn1556-f1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2a6c/9094669/bbad082d823d/sciadv.abn1556-f2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2a6c/9094669/b1cd58909ab4/sciadv.abn1556-f3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2a6c/9094669/e4dd09ed4a98/sciadv.abn1556-f4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2a6c/9094669/5edf0410e4d5/sciadv.abn1556-f5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2a6c/9094669/d2ac8c41d195/sciadv.abn1556-f6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2a6c/9094669/0e441e8128c0/sciadv.abn1556-f7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2a6c/9094669/97d7dcc28116/sciadv.abn1556-f8.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/2a6c/9094669/4d19d7d69b29/sciadv.abn1556-f9.jpg

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本文引用的文献

[1]
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