GDF11 protects against mitochondrial-dysfunction-dependent NLRP3 inflammasome activation to attenuate osteoarthritis,Journal of Advanced Research

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GDF11 protects against mitochondrial-dysfunction-dependent NLRP3 inflammasome activation to attenuate osteoarthritis
Journal of Advanced Research ( IF 11.4 ) Pub Date : 2024-08-03 , DOI: 10.1016/j.jare.2024.08.001
Pengfei Zhang ₁ , Haoxin Zhai ₁ , Shuai Zhang ₂ , Xiaojie Ma ₃ , Ao Gong ₄ , Zhaoning Xu ₅ , Wei Zhao ₆ , Hui Song ₆ , Shufeng Li ₇ , Tengfei Zheng ₈ , Zhendong Ying ₉ , Lei Cheng ₂ , Yunpeng Zhao ₂ , Lei Zhang ₁₀

Affiliation

Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, Shandong 250012, PR China; Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, PR China.
Department of Orthopedics, Qilu Hospital of Shandong University, Jinan, Shandong 250012, PR China.
Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250012, PR China; Department of Rheumatology and Immunology, Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250012, PR China.
Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250012, PR China; Second Clinical Medical College of Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250012, PR China.
Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, PR China.
Key Laboratory for Experimental Teratology of the Chinese Ministry of Education, and Key Laboratory of Infection and Immunity of Shandong Province, Jinan, Shandong 250012, PR China; School of Basic Medical Science, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, PR China.
Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250012, PR China; Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Jinan, Shandong 250012, PR China.
Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250012, PR China.
Second Clinical Medical College of Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250012, PR China.
Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, Shandong 250012, PR China; Shandong Key Laboratory of Rheumatic Disease and Translational Medicine, Jinan, Shandong 250012, PR China; Tissue Engineering Laboratory, Department of Radiology, Shandong First Medical University, PR China.

Introduction

Osteoarthritis (OA) is a highly prevalent degenerative disease worldwide, and tumor necrosis factor (TNF-α) is closely associated with its development. Growth differentiation factor 11 (GDF11) has demonstrated anti-injury and anti-aging abilities in certain tissues; however, its regulatory role in OA remains unclear and requires further investigation.

Objectives

To identify whether GDF11 can attenuate osteoarthritis. To exploring the the potential mechanism of GDF11 in alleviating osteoarthritis.

Methods

In this study, we cultured and stimulated mouse primary chondrocytes with or without TNF-α, analyzing the resulting damage phenotype through microarray analysis. Additionally, we employed GDF11 conditional knockout mice OA model to examine the relationship between GDF11 and OA. To investigate the target of GDF11′s function, we utilized NLRP3 knockout mice and its inhibitor to verify the potential involvement of the NLRP3 inflammasome.

Results

Our in vitro experiments demonstrated that endogenous overexpression of GDF11 significantly inhibited TNF-α-induced cartilage matrix degradation and inflammatory expression in chondrocytes. Furthermore, loss of GDF11 led to NLRP3 inflammasome activation, inflammation, and metabolic dysfunction. In an in vivo surgically induced mouse model, intraarticular administration of recombinant human GDF11 alleviated OA pathogenesis, whereas GDF11 conditional knockout reversed this effect. Additionally, findings from the NLRP3-knockout DMM mouse model revealed that GDF11 exerted its protective effect by inhibiting NLRP3.

Conclusion

These findings demonstrate the ability of GDF11 to suppress TNF-α-induced inflammation and cartilage degeneration by preventing mitochondrial dysfunction and inhibiting NLRP3 inflammasome activation, suggesting its potential as a promising therapeutic drug for osteoarthritis.

中文翻译：

GDF11 可防止线粒体功能障碍依赖性 NLRP3 炎性小体激活以减轻骨关节炎

介绍

骨关节炎（OA）是世界范围内高度普遍的退行性疾病，肿瘤坏死因子（TNF-α）与其发展密切相关。生长分化因子 11 （GDF11）已在某些组织中显示出抗损伤和抗衰老能力;然而，它在 OA 中的监管作用仍不清楚，需要进一步调查。

目标

确定 GDF11 是否可以减轻骨关节炎。探讨 GDF11 缓解骨关节炎的潜在机制。

方法

在这项研究中，我们培养和刺激有或没有 TNF-α的小鼠原代软骨细胞，通过微阵列分析产生的损伤表型。此外，我们采用 GDF11 条件性敲除小鼠 OA 模型来检验 GDF11 与 OA 之间的关系。为了研究 GDF11 功能的靶点，我们利用 NLRP3 敲除小鼠及其抑制剂来验证 NLRP3 炎性小体的潜在参与。

结果

我们的体外实验表明，GDF11 的内源性过表达显着抑制 TNF α诱导的软骨细胞软骨基质降解和炎症表达。此外，GDF11 的缺失导致 NLRP3 炎性小体激活、炎症和代谢功能障碍。在体内手术诱导的小鼠模型中，关节内施用重组人 GDF11 减轻了 OA 发病机制，而 GDF11 条件性敲除逆转了这种作用。此外，NLRP3 敲除 DMM 小鼠模型的发现显示，GDF11 通过抑制 NLRP3 发挥其保护作用。