Department of Orthopedics, Henan Provincial People's Hospital, Peolple's Hospital of Zhengzhou University, Zhengzhou, China.
Department of Orthopedics, Zhongda Hospital, Southeast University, Nanjing, China.
Int Immunopharmacol. 2024 Dec 25;143(Pt 2):113434. doi: 10.1016/j.intimp.2024.113434. Epub 2024 Oct 22.
Yes-associated protein 1 (YAP1) is a crucial downstream effector of the Hippo pathway that plays a role in regulating inflammation and mitochondrial function. However, whether YAP1 regulates pyroptosis in nucleus pulposus (NP) cells caused by inflammation via mitophagy remains unclear. This study aimed to investigate the effects of YAP1 on the pyroptosis of NP cells induced by LPS. Here, we demonstrated that the protein expression of YAP1 in the NP tissue of degenerative discs was significantly reduced. Next, we found that NLRP3 inflammasome activation in YAP1-overexpressing (YAP1-ov) NP cells was further enhanced in the LPS-induced inflammatory microenvironment. YAP1-ov strongly aggravated inflammation-induced pyroptosis and senescence, but these effects were reversed by the inhibition of BNIP3-mediated mitophagy. However, comparative analysis of the overexpression of YAP1 in normal discs and discs after annulus fibrosus puncture revealed that YAP1-ov accelerated the degeneration of normal discs and attenuated the degeneration of annulus fibrosus punctured discs in vivo. Additionally, YAP1-ov upregulated the expression of TNFAIP3, an anti-inflammatory protective protein, and CLPP, a vital protein in the mitochondrial unfolded protein response, in NP cells. Collectively, the above results revealed that YAP1 exacerbates LPS-induced pyroptosis and senescence of NP cells by promoting BNIP3-mediated mitophagy, which causes disc degeneration. Notably, YAP1-ov mitigated the degeneration of the disc caused by annular needle puncture in vivo, suggesting its potential as a therapeutic candidate foracute IDD injury.
Yes 相关蛋白 1（YAP1）是 Hippo 通路的关键下游效应物，在调节炎症和线粒体功能中发挥作用。然而，YAP1 是否通过线粒体自噬调节炎症引起的核髓核（NP）细胞焦亡尚不清楚。本研究旨在研究 YAP1 对 LPS 诱导的 NP 细胞焦亡的影响。在这里，我们证明了退变椎间盘 NP 组织中 YAP1 的蛋白表达显著降低。接下来，我们发现 LPS 诱导的炎症微环境中，YAP1 过表达（YAP1-ov）NP 细胞中 NLRP3 炎性体激活进一步增强。YAP1-ov 强烈加重炎症诱导的焦亡和衰老，但 BNIP3 介导的线粒体自噬抑制逆转了这些作用。然而，对正常椎间盘和纤维环穿刺后椎间盘 YAP1 过表达的比较分析表明，YAP1-ov 加速了正常椎间盘的退变，并在体内减轻了纤维环穿刺椎间盘的退变。此外，YAP1-ov 上调了 NP 细胞中 TNFAIP3（一种抗炎保护蛋白）和 CLPP（线粒体未折叠蛋白反应中的重要蛋白）的表达。综上所述，上述结果表明，YAP1 通过促进 BNIP3 介导的线粒体自噬加剧 LPS 诱导的 NP 细胞焦亡和衰老，导致椎间盘退变。值得注意的是，YAP1-ov 减轻了体内环状针穿刺引起的椎间盘退变，表明其作为急性 IDD 损伤的治疗候选物具有潜力。
