Department of Orthopaedics, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, #3 East Qingchun Road, Hangzhou 310016, China; Key Laboratory of Biotherapy of Zhejiang Province, #3 East Qingchun Road, Hangzhou 310016, China; Department of Orthopaedics, Huzhou Hospital, Zhejiang University, #198 Hongqi Road, Huzhou 313003, China.
Department of Orthopaedics, Sir Run Run Shaw Hospital, School of Medicine, Zhejiang University, #3 East Qingchun Road, Hangzhou 310016, China; Key Laboratory of Biotherapy of Zhejiang Province, #3 East Qingchun Road, Hangzhou 310016, China.
Free Radic Biol Med. 2018 May 20;120:368-379. doi: 10.1016/j.freeradbiomed.2018.04.008. Epub 2018 Apr 9.
Intervertebral disc degeneration (IVDD) is a multifactorial disease and responsible for many spine related disorders, causes disability in the workforce and heavy social costs all over the world. Honokiol, a low molecular weight natural product, could penetrate into and distribute in IVDs to achieve therapeutic effect in a rat tail model. Therefore, the present study was undertaken to examine the antiinflammatory, antioxidation and IVD-protective effect of honokiol using nucleus pulposus cells and investigate its mechanisms to provide a new basis for future clinical treatment of IVDD. In the current study, we demonstrated that honokiol inhibits the HO-induced apoptosis (caspase-9, caspase-3, and bax), levels of oxidative stress mediators (ROS, MDA), expression of inflammatory mediators (Interleukin-6, COX-2, and iNOS), major matrix degrading proteases (MMP-3, MMP-13, ADAMTS5, and ADAMTS4) associated with nucleus pulposus degradation. Furthermore, we found nucleus pulposus protective ability of honokiol by up-regulating extra cellular matrix anabolic factors like type II collagen (Col II) and SOX9 in nucleus pulposus. We also found that honokiol suppressed the phosphorylation of NF-kB and JNK, and activation of TXNIP-NLRP3 inflammasome in HO-stimulated nucleus pulposus cells, thereby inhibiting the activation of downstream inflammatory mediators such as Interleukin-1β. Furthermore, honokiol showed a cartilage protective effect in the progression of IVDD in a rat model induced by puncture. Thus, our results demonstrate that honokiol inhibited the HO induced apoptosis, oxidative stress, and inflammatory responses through the depression of TXNIP/NLRP3/caspase-1/ Interleukin - 1β signaling axis and the activation of NF-kB and JNK. Honokiol possess nucleus pulposus protective properties and may be of value in suppressing the pathogenesis of IVDD.
椎间盘退变（IVDD）是一种多因素疾病，可导致许多与脊柱相关的疾病，使劳动力丧失能力，并在全球造成沉重的社会成本。和厚朴酚是一种低分子量天然产物，能够穿透并分布在椎间盘内，从而在大鼠尾模型中达到治疗效果。因此，本研究旨在通过髓核细胞研究和厚朴酚的抗炎、抗氧化和椎间盘保护作用，并探讨其机制，为未来 IVDD 的临床治疗提供新的依据。在本研究中，我们证明了和厚朴酚抑制 HO 诱导的细胞凋亡（半胱天冬酶-9、半胱天冬酶-3 和 bax）、氧化应激介质（ROS、MDA）、炎症介质（白细胞介素-6、COX-2 和 iNOS）、主要基质降解蛋白酶（MMP-3、MMP-13、ADAMTS5 和 ADAMTS4）的水平，这些物质与椎间盘退化有关。此外，我们发现和厚朴酚通过上调细胞外基质合成因子，如 II 型胶原（Col II）和 SOX9，从而具有保护髓核的能力。我们还发现，和厚朴酚抑制了 HO 刺激的髓核细胞中 NF-kB 和 JNK 的磷酸化以及 TXNIP-NLRP3 炎性小体的激活，从而抑制了下游炎症介质如白细胞介素-1β的激活。此外，和厚朴酚在 HO 诱导的大鼠椎间盘退变模型中表现出软骨保护作用。因此，我们的研究结果表明，和厚朴酚通过抑制 TXNIP/NLRP3/caspase-1/白细胞介素-1β信号通路以及激活 NF-kB 和 JNK，抑制 HO 诱导的细胞凋亡、氧化应激和炎症反应，从而发挥抑制 IVDD 发病机制的作用。和厚朴酚具有保护髓核的特性，可能对抑制 IVDD 的发病机制具有重要意义。
