Cell type-specific effects of Notch signaling activation on intervertebral discs: Implications for intervertebral disc degeneration.
Cell type-specific effects of Notch signaling activation on intervertebral discs: Implications for intervertebral disc degeneration.
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DOI：
10.1002/jcp.26385
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发表时间：
2018-07
影响因子：
5.6
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Zheng Y;Liu C;Ni L;Liu Z;Mirando AJ;Lin J;Saijilafu;Chen D;Hilton MJ;Li B;Chen J
椎间盘退变是引起背痛的主要原因。Notch信号在退变IVD的纤维环（AF）和髓核（NP）组织中被激活，并在NP细胞中被IL 1-β和TNF-α诱导。然而，Notch激活在IVD变性发病机制中的作用在很大程度上是未知的。在这项研究中，我们通过腺病毒在AF、NP和软骨形成ATDC 5细胞中过表达Notch 1胞内结构域（NICD 1）。在AF、NP和ATDC 5细胞中，NICD 1的过表达激活Notch信号传导靶基因的转录，并对基质合成代谢和分解代谢基因的表达造成细胞类型特异性影响。Notch信号的激活促进AF和ATDC 5细胞中基质分解代谢基因的表达并抑制基质合成代谢基因的表达，而其激活抑制NP细胞中基质分解代谢基因（包括Mmp 3、Mmp 13、Adamts 4和Adamts 5）的表达并减弱TNF-α和炎性巨噬细胞诱导的Mmp 13表达。一致地，在小鼠出生后IVD中持续激活Notch 1信号严重破坏生长板和终板软骨组织，但没有过度影响NP组织。总之，这些数据表明，Notch信号的激活在椎间盘中产生了差异性和细胞类型特异性效应，并且在IVD退变的治疗期间可以考虑特异性Notch信号调节。
Intervertebral disc (IVD) degeneration is the major cause of back pain. Notch signaling is activated in annulus fibrosus (AF) and nucleus pulposus (NP) tissues of degenerated IVDs, and induced by IL1-β and TNF-α in NP cells. However, the role of Notch activatin in the pathogenesis of IVD degeneration is largely unknown. In this study, we overexpressed the Notch1 intracellular domain (NICD1) in AF, NP, and chondrogenic ATDC5 cells via adenoviruses. Over-expression of NICD1 activated transcription of Notch signaling target genes in AF, NP, and ATDC5 cells, and caused cell type-specific effects on expression of matrix anabolic and catabolic genes. Activation of Notch signaling promoted expression of matrix catabolic genes and inhibited expression of matrix anabolic genes in both AF and ATDC5 cells, whereas its activation suppressed expression of matrix catabolic genes (including Mmp3, Mmp13, Adamts4, and Adamts5) and attenuated TNF-α and inflammatory macrophage-induced Mmp13 expression in NP cells. Consistently, sustained activation of Notch1 signaling in postnatal IVDs in mice severely disrupted growth plate and endplate cartilage tissues, but did not overly affect NP tissues. Together, these data indicated that activation of Notch signaling exerted differential and cell type-specific effects in intervertebral discs, and specific Notch signaling regulation may be considered during the treatment of IVD degeneration.
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影响因子：
5.6
作者：
Kim, Jae-Sung;Ellman, Michael B.;Yan, Dongyao;An, Howard S.;Ranjan, K. C.;Li, Xin;Chen, Di;Xiao, Guozhi;Cs-Szabo, Gabriella;Hoskin, David W.;Buechter, Doug D.;Van Wijnen, Andre J.;Im, Hee-Jeong
通讯作者：
Im, Hee-Jeong
影响因子：
12.7
作者：
Chen D;Shen J;Zhao W;Wang T;Han L;Hamilton JL;Im HJ
通讯作者：
Im HJ
影响因子：
--
作者：
Mirando, Anthony J.;Liu, Zhaoyang;Moore, Tyler;Lang, Alexandra;Kohn, Anat;Osinski, Alana M.;O'Keefe, Regis J.;Mooney, Robert A.;Zuscik, Michael J.;Hilton, Matthew J.
通讯作者：
Hilton, Matthew J.
使用 Noto-cre 小鼠追踪脊索衍生细胞：对椎间盘发育的影响。
影响因子：
4.3
作者：
McCann MR;Tamplin OJ;Rossant J;Séguin CA
通讯作者：
Séguin CA
影响因子：
2.8
作者：
Bron, Johannes Leendert;Helder, Marco N.;Meisel, Hans-Jorg;Royen, Barend J. Van;Smit, Theodoor H.
通讯作者：
Smit, Theodoor H.