Cell type‐specific effects of Notch signaling activation on intervertebral discs: Implications for intervertebral disc degeneration

Jul 21, 2018Journal of cellular physiology

How activating Notch signaling affects different cell types in spinal discs and its link to disc degeneration

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Abstract

Notch signaling activation in intervertebral discs may have differential effects on cell types involved in degeneration.

Activation of Notch signaling was induced by IL1-β and TNF-α in nucleus pulposus cells.
Overexpression of the Notch1 intracellular domain (NICD1) in various cell types activated target genes associated with Notch signaling.
In annulus fibrosus and chondrogenic cells, Notch signaling activation increased the expression of matrix catabolic genes while decreasing anabolic gene expression.
In contrast, activation of Notch signaling in nucleus pulposus cells suppressed matrix catabolic gene expression.
Sustained Notch1 signaling activation in postnatal mice disrupted growth plate and endplate cartilage tissues but had a lesser effect on nucleus pulposus tissues.

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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. Overexpression 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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