JAG2/Notch2 inhibits intervertebral disc degeneration by modulating cell proliferation, apoptosis, and extracellular matrix
JAG2/Notch2 inhibits intervertebral disc degeneration by modulating cell proliferation, apoptosis, and extracellular matrix
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JAG2/Notch2 通过调节细胞增殖、凋亡和细胞外基质抑制椎间盘退变
DOI：
10.1186/s13075-019-1990-z
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发表时间：
2019-10-16
影响因子：
4.9
通讯作者：
Zheng, Zhaomin
中科院分区：
文献类型：
--
作者：
Long, Jun;Wang, Xiaobo;Zheng, Zhaomin
背景椎间盘退变（IVDD）相关疾病是引起下腰痛的主要原因.先前的一项研究表明，Notch激活作为一种保护机制，是维持必要的常驻髓核（NP）细胞增殖以取代丢失或无功能细胞的代偿反应的一部分。然而，确切的机制仍有待确定。在这项研究中，我们的目的是研究JAG 2/Notch 2在NP细胞增殖和凋亡中的作用。方法重组JAG 2或Notch 2，Hes 1和Hey 2 siRNA被用来激活或抑制Notch信号。检测细胞增殖、凋亡、细胞周期调控因子以及与Notch介导的增殖相关的途径。在体内实验涉及椎间盘内注射的Sprague-Dawley大鼠performed.ResultsRecombinant JAG 2诱导Notch 2和Hes 1/Hey 2的表达与NP细胞增殖。下调Notch 2/Hes 1/Hey 2的表达可使NP细胞阻滞于G 0/G1期。此外，Notch 2通过调控cyclin D1和激活PI 3 K/Akt和Wnt/β-catenin信号通路介导NP细胞增殖。Notch信号通过抑制RIP 1-FADD-caspase-8复合物的形成，抑制TNF-α诱导的NP细胞凋亡。最后，我们发现椎间盘内注射JAG 2减轻了大鼠模型中的IVDD，而sh-Notch 2加重了IVDD。这些结果表明JAG 2/Notch 2通过调节细胞增殖、凋亡和细胞外基质来抑制IVDD。JAG 2/Notch 2轴通过PI 3 K/Akt和Wnt/β-catenin信号调节NP细胞增殖，并通过抑制RIP 1-FADD-caspase-8复合物的形成抑制TNF-α诱导的细胞凋亡。
BackgroundIntervertebral disc degeneration (IVDD)-related disorders are the major causes of low back pain. A previous study suggested that Notch activation serves as a protective mechanism and is a part of the compensatory response that maintains the necessary resident nucleus pulposus (NP) cell proliferation to replace lost or non-functional cells. However, the exact mechanism remains to be determined. In this study, we aimed to investigate the role of JAG2/Notch2 in NP cell proliferation and apoptosis.MethodsRecombinant JAG2 or Notch2, Hes1, and Hey2 siRNAs were used to activate or inhibit Notch signaling. Cell proliferation, apoptosis, cell cycle regulatory factors, and pathways associated with Notch-mediated proliferation were examined. In vivo experiments involving an intradiscal injection of Sprague-Dawley rats were performed.ResultsRecombinant JAG2 induced Notch2 and Hes1/Hey2 expression together with NP cell proliferation. Downregulation of Notch2/Hes1/Hey2 induced G0/G1 phase cell cycle arrest in NP cells. Moreover, Notch2 mediated NP cell proliferation by regulating cyclin D1 and by activating PI3K/Akt and Wnt/β-catenin signaling. Furthermore, Notch signaling inhibited TNF-α-promoted NP cell apoptosis by suppressing the formation of the RIP1-FADD-caspase-8 complex. Finally, we found that intradiscal injection of JAG2 alleviated IVDD and that sh-Notch2 aggravated IVDD in a rat model. These results indicated that JAG2/Notch2 inhibited IVDD by modulating cell proliferation, apoptosis, and extracellular matrix. The JAG2/Notch2 axis regulated NP cell proliferation via PI3K/Akt and Wnt/β-catenin signaling and inhibited TNF-α-induced apoptosis by suppressing the formation of the RIP1-FADD-caspase-8 complex.ConclusionsThe current and previous results shed light on the therapeutic implications of targeting the JAG2/Notch2 axis to inhibit or reverse IVDD.