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Inhibition of OLR1 reduces SASP of nucleus pulposus cells by targeting autophagy-GATA4 axis
The Journals of Gerontology Series A: Biological Sciences and Medical Sciences ( IF 4.3 ) Pub Date : 2024-08-22 , DOI: 10.1093/gerona/glae204
Jia-Wei Gao 1 , Hang Shi 1 , Fu-Ping Gao 2 , Zhi-Min Zhou 1 , Xin Peng 1 , Rui Sun 1 , V L F Cabral 1 , Jian Li 3 , Yun-Tao Wang 1, 3 , Xiao-Hu Wang 1 , Xiao-Tao Wu 1
The Journals of Gerontology Series A: Biological Sciences and Medical Sciences ( IF 4.3 ) Pub Date : 2024-08-22 , DOI: 10.1093/gerona/glae204
Jia-Wei Gao 1 , Hang Shi 1 , Fu-Ping Gao 2 , Zhi-Min Zhou 1 , Xin Peng 1 , Rui Sun 1 , V L F Cabral 1 , Jian Li 3 , Yun-Tao Wang 1, 3 , Xiao-Hu Wang 1 , Xiao-Tao Wu 1
Affiliation
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.
中文翻译:
抑制 OLR1 通过靶向自噬-GATA4 轴降低髓核细胞的 SASP
近年来,通过自噬靶向细胞衰老和衰老相关分泌表型 (SASP) 已成为一种很有前途的椎间盘 (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。方法涉及对正常和 IDD 患者的髓核 (NP) 组织以及体内 IDD 动物模型进行体外实验。GATA4 在 SASP 中的调节作用在体外和体内均得到验证,同时自噬调节剂用于评估它们对 GATA4 和 SASP 的影响。转录组测序确定氧化低密度脂蛋白受体 1 (OLR1) 是自噬和 GATA4 的关键调节因子。一系列实验操纵 OLR1 表达以研究相关效应。结果显示 IDD 患者和动物模型中衰老的 NP 细胞 (NPC) 显著增加,自噬受损,SASP 与 IDD 进展密切相关。衰老的椎间盘环境阻碍了自噬 GATA4 降解,导致衰老 NPC 中 SASP 表达升高。恢复自噬通过降解 GATA4 逆转衰老,从而破坏 SASP 级联反应。此外,OLR1 在衰老 NPC 中对自噬和 GATA4 的调节被鉴定出来。沉默 OLR1 增强了自噬活性,抑制了 GATA4 诱导的衰老和衰老 SASP 表达。总之,发现 OLR1 控制自噬-GATA4 和 SASP,靶向抑制 OLR1 有望减轻 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。
更新日期:2024-08-22
中文翻译:
抑制 OLR1 通过靶向自噬-GATA4 轴降低髓核细胞的 SASP
近年来,通过自噬靶向细胞衰老和衰老相关分泌表型 (SASP) 已成为一种很有前途的椎间盘 (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。方法涉及对正常和 IDD 患者的髓核 (NP) 组织以及体内 IDD 动物模型进行体外实验。GATA4 在 SASP 中的调节作用在体外和体内均得到验证,同时自噬调节剂用于评估它们对 GATA4 和 SASP 的影响。转录组测序确定氧化低密度脂蛋白受体 1 (OLR1) 是自噬和 GATA4 的关键调节因子。一系列实验操纵 OLR1 表达以研究相关效应。结果显示 IDD 患者和动物模型中衰老的 NP 细胞 (NPC) 显著增加,自噬受损,SASP 与 IDD 进展密切相关。衰老的椎间盘环境阻碍了自噬 GATA4 降解,导致衰老 NPC 中 SASP 表达升高。恢复自噬通过降解 GATA4 逆转衰老,从而破坏 SASP 级联反应。此外,OLR1 在衰老 NPC 中对自噬和 GATA4 的调节被鉴定出来。沉默 OLR1 增强了自噬活性,抑制了 GATA4 诱导的衰老和衰老 SASP 表达。总之,发现 OLR1 控制自噬-GATA4 和 SASP,靶向抑制 OLR1 有望减轻 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。