Stabilization of hypoxia-inducible factor-1α is involved in the hypoxic stimuli-induced expression of vascular endothelial growth factor in osteoblastic cells

Hong Hee Kim, Shee Eun Lee, Woon Jae Chung, Youngyeon Choi, Kyubum Kwack, Si Wouk Kim, Myong Soo Kim, Hyunsung Park, Zang Hee Lee

Research output: Contribution to journalArticlepeer-review

80 Scopus citations

Abstract

It has been suggested that blood vessel formation is an important event coupled to bone formation. The expression of vascular endothelial growth factor (VEGF), a potent angiogenic factor, has been shown to be greatly stimulated in osteoblasts by hypoxic stimuli such as deprivation of oxygen and treatment with cobalt. In other cell types, hypoxia-inducible factor-1 (HIF-1) that binds hypoxia-response element (HRE) has been shown to mediate gene expression induced by hypoxic stimuli. In this study, we investigated the effects of hypoxic stimuli on HIF-1, HRE, and VEGF in osteoblastic cell lines. Exposure of these cells to hypoxia or cobalt resulted in a great increase in the protein level of HIF-1α and the gene expression of VEGF. Transforming growth factor-β1, prostaglandin E2, dexamethasone, and 1,25-dihydroxyvitamin D3 that have been shown to regulate VEGF gene expression in osteoblasts had no effect on HIF-1α induction. Blocking the enzymatic activity of phosphatidylinositol 3-kinase, p38, MEK-1 did not have any effect on the cobalt-stimulated increase of HIF-1α in these cells. In contrast, N-acetylcysteine (NAC), a scavenger of reactive oxygen species, abolished the cobalt induction of HIF-1α and that of the VEGF and a HRE-driven reporter genes. However, the hypoxia responses were not affected by NAC. These findings suggest that hypoxia and cobalt can induce VEGF gene expression in osteoblasts by increasing the level of HIF-1α protein through different mechanisms.

Original languageEnglish
Pages (from-to)14-27
Number of pages14
JournalCytokine
Volume17
Issue number1
DOIs
StatePublished - 2002

Keywords

  • Hypoxia
  • Hypoxia-inducible factor-1α
  • Osteoblast
  • Reactive oxygen species
  • Vascular endothelial growth factor

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