Hypoxia-inducible factor-lα mediates aggrecan and collagen Π expression via NOTCH1 signaling in nucleus pulposus cells during intervertebral disc degeneration

Biochemical and Biophysical Research Communications
Zhuochao LiuXingkai Zhang

Abstract

Although hypoxia-inducible factor-lα (HIF-lα) 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-1α-/- mice. Our study reveals that overexpression of HIF-1α 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 Π 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 Π and aggrecan expression, inhibition of the HIF-1α-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 Π and aggrecan expression. Therefore, our study shows that HIF-1α regulates ...Continue Reading

Citations

Apr 4, 2020·Journal of Orthopaedic Research : Official Publication of the Orthopaedic Research Society·Tomonori ItsujiToshikazu Kubo
May 30, 2020·Experimental & Molecular Medicine·Bao HuangFengdong Zhao
Aug 23, 2019·Molecular Medicine Reports·Jinwen ZhuDingjun Hao
Jan 2, 2019·Journal of Biological Engineering·Zhuochao LiuXingkai Zhang
Sep 27, 2018·Journal of Inflammation·Kuo-Yuan HuangRuey-Mo Lin
Apr 5, 2021·Biochemical and Biophysical Research Communications·Jiancheng ZhengLianfu Deng
Aug 7, 2021·Frontiers in Bioengineering and Biotechnology·Yiming DouQiang Yang

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