骨蛋白缺乏症通过增强 NF-κB 信号来招募巨噬细胞并激活 NLRP3 炎性体,从而促进软骨终板退化

IF 14.3 1区 医学 Q1 CELL & TISSUE ENGINEERING Bone Research Pub Date : 2024-09-06 DOI:10.1038/s41413-024-00355-3
Yanqiu Wang, Wanqian Zhang, Yi Yang, Jinghao Qin, Ruoyu Wang, Shuai Wang, Wenjuan Fu, Qin Niu, Yanxia Wang, Changqing Li, Hongli Li, Yue Zhou, Minghan Liu
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引用次数: 0

摘要

椎间盘退变(IDD)是椎间盘源性疼痛的主要原因,是由于髓核、纤维环和软骨终板(CEP)的功能障碍造成的。骨蛋白(OPN)是一种糖蛋白,在 CEP 中高度表达。然而,人们对 OPN 如何调节 CEP 的稳态和变性,从而导致 IDD 的发病机制知之甚少。在此,我们研究了腰椎不稳诱导的小鼠IDD模型中OPN在CEP变性中的作用及其在病理条件下对终板软骨细胞(EPCs)变性的影响。OPN主要在CEP中表达,并随着小鼠和人类严重IDD患者的退化而减少。成年小鼠EPCs中的条件性Spp1基因敲除增强了与年龄相关的CEP退化,并加速了IDD期间的CEP重塑。从机理上讲,OPN的缺乏会增加EPCs中CCL2和CCL5的产生,从而招募巨噬细胞,并通过促进IRAK1-TRAF6复合物的组装,增强NLRP3炎性体和NF-κB信号的激活,以时空模式恶化CEP变性。更重要的是,药物抑制 NF-κB/NLRP3 轴可减轻 OPN 缺失 IDD 小鼠的 CEP 退化。总之,这项研究强调了OPN在维持CEP和椎间盘稳态中的重要性,并提出了一种通过靶向NF-κB/NLRP3轴治疗IDD的有前途的治疗策略。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Osteopontin deficiency promotes cartilaginous endplate degeneration by enhancing the NF-κB signaling to recruit macrophages and activate the NLRP3 inflammasome

Intervertebral disc degeneration (IDD) is a major cause of discogenic pain, and is attributed to the dysfunction of nucleus pulposus, annulus fibrosus, and cartilaginous endplate (CEP). Osteopontin (OPN), a glycoprotein, is highly expressed in the CEP. However, little is known on how OPN regulates CEP homeostasis and degeneration, contributing to the pathogenesis of IDD. Here, we investigate the roles of OPN in CEP degeneration in a mouse IDD model induced by lumbar spine instability and its impact on the degeneration of endplate chondrocytes (EPCs) under pathological conditions. OPN is mainly expressed in the CEP and decreases with degeneration in mice and human patients with severe IDD. Conditional Spp1 knockout in EPCs of adult mice enhances age-related CEP degeneration and accelerates CEP remodeling during IDD. Mechanistically, OPN deficiency increases CCL2 and CCL5 production in EPCs to recruit macrophages and enhances the activation of NLRP3 inflammasome and NF-κB signaling by facilitating assembly of IRAK1-TRAF6 complex, deteriorating CEP degeneration in a spatiotemporal pattern. More importantly, pharmacological inhibition of the NF-κB/NLRP3 axis attenuates CEP degeneration in OPN-deficient IDD mice. Overall, this study highlights the importance of OPN in maintaining CEP and disc homeostasis, and proposes a promising therapeutic strategy for IDD by targeting the NF-κB/NLRP3 axis.

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来源期刊
Bone Research
Bone Research CELL & TISSUE ENGINEERING-
CiteScore
20.00
自引率
4.70%
发文量
289
审稿时长
20 weeks
期刊介绍: Established in 2013, Bone Research is a newly-founded English-language periodical that centers on the basic and clinical facets of bone biology, pathophysiology, and regeneration. It is dedicated to championing key findings emerging from both basic investigations and clinical research concerning bone-related topics. The journal's objective is to globally disseminate research in bone-related physiology, pathology, diseases, and treatment, contributing to the advancement of knowledge in this field.
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