TDP-43 maintains chondrocyte homeostasis and alleviates cartilage degradation in osteoarthritis
TDP-43 maintains chondrocyte homeostasis and alleviates cartilage degradation in osteoarthritis
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TDP-43 维持软骨细胞稳态并减轻骨关节炎中的软骨退化
DOI：
10.1016/j.joca.2021.03.015
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发表时间：
2021-06-17
影响因子：
7
通讯作者：
Shi, D.
中科院分区：
文献类型：
--
作者：
Chang, L.;Liu, A.;Shi, D.
目的：骨关节炎（Osteoarthritis，OA）是最常见的与年龄相关的软骨退化性疾病。先前的研究已经确定了细胞外应力下软骨细胞稳态的异常是OA软骨降解的关键病理机制。TDP-43是一种DNA/RNA结合蛋白，已被证明参与许多细胞外应激反应的处理;然而，对TDP-43在OA中的作用的理解是有限的。本研究旨在探讨TDP-43在OA软骨细胞稳态和软骨降解中的作用。方法：通过实验性创伤后OA动物模型和人软骨标本来研究TDP-43在软骨降解过程中的作用。通过组织学分析、qPCR和蛋白质印迹评估胡萝卜素降解。使用人原代软骨细胞在体外研究分子机制。结果：TDP-43在退变软骨中显著减少。OA患者滑液中TDP-43浓度与IL-1b浓度呈正相关（Pearson r = 0.95，CI（95%）[0.80，0.99]，P < 0.0001）。关节内注射重组TDP-43可显著减轻体内软骨降解和软骨下骨重建。体外机制分析表明，TDP-43通过G3 BP 1调节应激颗粒动力学，维持氧化应激下软骨细胞的稳态。结论：目前的研究表明，TDP-43在氧化应激下维持软骨细胞稳态，并抑制骨关节炎中的软骨退化，将TDP-43确定为诊断和治疗膝关节OA的潜在靶点。(c)2021国际骨关节炎研究学会。由爱思唯尔有限公司出版。保留所有权利。
Objective: Osteoarthritis (OA) is the most prevalent age-related disorder due to cartilage degradation. Previous studies have identified aberrant chondrocyte homeostasis under extracellular stress as a key pathological mechanism behind cartilage degradation in OA. TDP-43, a DNA/RNA-binding protein has been demonstrated to participate in processing many extracellular stress responses; however, understanding of the role of TDP-43 in OA is limited. This study aims to investigate the role of TDP-43 in chondrocyte homeostasis and cartilage degradation in OA. Methods: The role of TDP-43 during degradation of cartilage is examined by experimental posttraumatic OA animal models and human cartilage specimens. Cartilage degradation is assessed by histological analysis, qPCR, and Western blot. The molecular mechanisms are investigated in vitro using human primary chondrocytes. Results: TDP-43 decreases significantly in degenerated cartilage. TDP-43 concentration is positively correlated with IL-1b concentration in synovial fluid derived from OA patients (Pearson r = 0.95, CI (95%) [0.80, 0.99], P < 0.0001). Intra-articular injection of recombinant TDP-43 significantly alleviates cartilage degradation and subchondral bone remodeling in vivo. In vitro mechanistic analyses show that TDP-43 maintains chondrocyte homeostasis under oxidative stress through regulating stress granule dynamics via G3BP1. Conclusion: The present study indicates that TDP-43 maintains chondrocyte homeostasis under oxidative stress and alleviates cartilage degeneration in osteoarthritis, identifying TDP-43 as a potential target for the diagnosis and treatment of knee OA. (c) 2021 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.