Hypoxia-inducible factor-1α mediates aggrecan and collagen Π expression via NOTCH1 signaling in nucleus pulposus cells during intervertebral disc degeneration
Hypoxia-inducible factor-1α mediates aggrecan and collagen Π expression via NOTCH1 signaling in nucleus pulposus cells during intervertebral disc degeneration
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DOI：
10.1016/j.bbrc.2017.05.086
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发表时间：
2017-07-01
影响因子：
3.1
通讯作者：
Zhang, Xingkai
中科院分区：
文献类型：
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作者：
Liu, Zhuochao;Li, Changwei;Zhang, Xingkai
虽然低氧诱导因子-I α（HIF-1 α）已被报道在髓核细胞（NPC）的细胞外基质（ECM）的代谢和合成中具有重要作用，但其潜在机制尚未完全阐明。在这里，我们首次表明，NOTCH 1表达减少，从退化的人椎间盘（IVD）分离的NP，以及在NP特异性HIF-1 α（-/-）小鼠的NP。我们的研究表明，HIF-1 α的过表达导致NOTCH 1、NOTCH 1配体JAGGED 1及其靶基因hairy和分裂增强子1（HES 1）的表达增加，同时还上调了人NPC中的胶原Pi和聚集蛋白聚糖的表达。重要的是，这些表达变化被NOTCH 1抑制剂DAPT显著抑制。与胶原蛋白Pi和聚集蛋白聚糖表达的变化平行，HIF-1 α-NOTCH 1通路的抑制通过抑制基质金属蛋白酶MMP 1和MMP 13的表达而改变ECM的周转，同时增加金属蛋白酶组织抑制剂1（TIMP 1）的表达。最后，在从退化的IVD中分离的人NPC中通过JAGGED 1激活NOTCH 1恢复了胶原蛋白Pi和聚集蛋白聚糖的表达。因此，我们的研究表明，HIF-1 α通过NOTCH 1信号调节胶原Pi和聚集蛋白聚糖的表达，并暗示NOTCH 1是椎间盘退变的潜在治疗靶点。(C)2017作者（S）爱思唯尔公司出版
Although hypoxia-inducible factor-I alpha (HIF-I alpha) has been reported to have an important role in the metabolism and synthesis of the extracellular matrix (ECM) of nucleus pulposus cells (NPCs), the underlying mechanism has not been fully clarified. Here, we show for the first time that NOTCH1 expression is decreased in NPs isolated from degenerated human intervertebral discs (IVDs), as well as in the NPs of NP-specific HIF-1 alpha(-/-) mice. Our study reveals that overexpression of HIF-1 alpha leads to increased expression of NOTCH1, the NOTCH1 ligand JAGGED1, and its target gene hairy and enhancer of split-1 (HES1), while also upregulating collagen Pi and aggrecan expression in human NPCs. Importantly, these changes in expression are significantly suppressed by the NOTCH1 inhibitor DAPT. In parallel with changes in collagen Pi and aggrecan expression, inhibition of the HIF-1 alpha-NOTCH1 pathway altered ECM turnover by suppressing expression of the matrix metalloproteinases MMP1 and MMP13, while increasing the expression of tissue inhibitor of metalloproteinase-1 (TIMP1). Lastly, activation of NOTCH1 via JAGGED1 in human NPCs isolated from degenerated IVDs restored collagen Pi and aggrecan expression. Therefore, our study shows that HIF-1 alpha regulates collagen Pi and aggrecan expression through NOTCH1 signaling and implicate NOTCH1 as a potential therapeutic target in disc degeneration. (C) 2017 The Author(s). Published by Elsevier Inc.