抑制 OLR1 可通过靶向自噬-GATA4 轴减少髓核细胞的 SASP。

Jia-Wei Gao, Hang Shi, Fu-Ping Gao, Zhi-Min Zhou, Xin Peng, Rui Sun, V L F Cabral, Jian Li, Yun-Tao Wang, Xiao-Hu Wang, Xiao-Tao Wu
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引用次数: 0

摘要

近年来,通过自噬靶向细胞衰老和衰老相关分泌表型(SASP)已成为一种很有前景的椎间盘(IVD)变性(IDD)治疗策略。本研究旨在阐明自噬在预防 IVD SASP 中的作用和机制。研究方法包括利用正常和IDD患者的髓核组织进行体外实验,以及建立体内IDD动物模型。GATA4在SASP中的调控作用在体外和体内都得到了验证,同时采用自噬调节剂来评估它们对GATA4和SASP的影响。转录组测序发现氧化低密度脂蛋白受体1(OLR1)是自噬和GATA4的关键调控因子。一系列实验操纵了 OLR1 的表达,以研究其相关效应。结果表明,在IDD患者和动物模型中,衰老NP细胞(NPC)明显增加,自噬功能受到损害,SASP与IDD进展密切相关。老化的椎间盘环境阻碍了自噬GATA4的降解,导致衰老NPC中SASP的表达升高。恢复自噬可通过降解 GATA4 逆转衰老,从而破坏 SASP 级联。此外,OLR1还被鉴定为可调节衰老NPC中的自噬和GATA4。沉默 OLR1 可增强自噬活性,抑制 GATA4 诱导的衰老和衰老 NPC 中 SASP 的表达。总之,研究发现OLR1能控制自噬-GATA4和SASP,靶向抑制OLR1有望缓解GATA4诱导的衰老和SASP表达,同时延缓细胞外基质降解,为IDD管理提供了一种新的治疗方法。
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Inhibition of OLR1 reduces SASP of nucleus pulposus cells by targeting autophagy-GATA4 axis.

Targeting cellular senescence and Senescence Associated Secretory Phenotype (SASP) through autophagy has emerged as a promising intervertebral disc (IVD) degeneration (IDD) treatment strategy in recent years. This study aimed to clarify the role and mechanism of autophagy in preventing IVD SASP. Methods involved in vitro experiments with nucleus pulposus (NP) tissues from normal and IDD patients, as well as an in vivo IDD animal model. GATA4's regulatory role in SASP was validated both in vitro and in vivo, while autophagy modulators were employed to assess their impact on GATA4 and SASP. Transcriptomic sequencing identified Oxidized low-density lipoprotein receptor 1 (OLR1) as a key regulator of autophagy and GATA4. A series of experiments manipulated OLR1 expression to investigate associated effects. Results demonstrated significantly increased senescent NP cells (NPCs) and compromised autophagy in IDD patients and animal models, with SASP closely linked to IDD progression. The aged disc milieu impeded autophagic GATA4 degradation, leading to elevated SASP expression in senescent NPCs. Restoring autophagy reversed senescence by degrading GATA4, hence disrupting the SASP cascade. Moreover, OLR1 was identified for its regulation of autophagy and GATA4 in senescent NPCs. Silencing OLR1 enhanced autophagic activity, suppressing GATA4-induced senescence and SASP expression in senescent NPCs. In conclusion, OLR1 was found to control autophagy-GATA4 and SASP, with targeted OLR1 inhibition holding promise in alleviating GATA4-induced senescence and SASP expression while delaying extracellular matrix degradation, offering a novel therapeutic approach for IDD management.

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