1. Academic Validation
  2. Elevated expression of hypoxia-inducible factor-2alpha regulated catabolic factors during intervertebral disc degeneration

Elevated expression of hypoxia-inducible factor-2alpha regulated catabolic factors during intervertebral disc degeneration

  • Life Sci. 2019 Sep 1;232:116565. doi: 10.1016/j.lfs.2019.116565.
Yuelong Huang 1 Ying Wang 2 Chengai Wu 2 Wei Tian 3
Affiliations

Affiliations

  • 1 Department of Spine Surgery, Peking University Fourth School of Clinical Medicine, No. 31, Xinjiekou East Street, Xicheng District, Beijing 100035, China.
  • 2 Institute of Traumatology and Orthopaedics, Beijing Laboratory of Biomedical Materials, Beijing Jishuitan Hospital, No. 31, Xinjiekou East Street, Xicheng District, Beijing 100035, China.
  • 3 Department of Spine Surgery, Peking University Fourth School of Clinical Medicine, No. 31, Xinjiekou East Street, Xicheng District, Beijing 100035, China. Electronic address: tianwei123vip@163.com.
Abstract

Headings aims: The present study determined whether nucleus pulposus (NP) cells express hypoxia-inducible factor-2alpha (HIF-2α) and assessed its role in regulating the expression of catabolic factors during intervertebral disc degeneration.

Materials and methods: Human degenerated NP tissues were acquired to examine the HIF-2α expression levels using immunohistochemistry, western blotting, and Real-Time PCR. Human NP cells were cultivated under normoxic or hypoxic conditions, and the HIF-2α expression was determined. Then, human NP cells were treated with HIF-2α plasmids, HIF-2α siRNA, and tumor necrosis factor-alpha (TNF-α) to evaluate the role of HIF-2α in regulating matrix metalloproteinase (MMP) and aggrecanase expression. An in vivo rabbit disc degeneration model was established to demonstrate that HIF-2α plays a critical role in disc degeneration.

Key findings: We found that HIF-2α had a markedly elevated expression in human degenerated discs in the Grade III stage. HIF-2α protein and gene transcript levels in vitro were relatively higher under hypoxic conditions. The expression of MMP-13, ADAMTS-4 was decreased significantly in HIF-2α silencing condition, while the over-expression resulted in significantly increased levels of MMP-13 and ADAMTS-4. When cytokine TNF-α was added, HIF-2α was induced by nuclear factor-κB (NF-κB). The in vivo experiments showed that the HIF-2α controlled the catabolic factors MMP-13 and ADAMTS-4 that regulated the collagen II and aggrecan metabolism in disc degeneration.

Significance: HIF-2α is a catabolic regulator in disc degeneration and directly controls the catabolic genes. The suppression of HIF-2α expression leads to decelerates extracellular matrix degradation that might represent a therapeutic target for the degenerative disc.

Keywords

ADAMTS-4; HIF-2α; MMP-13; Nucleus pulposus.

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