Laquinimod inhibits the expression and function of hypoxia-inducible factor-2 alpha in osteoblasts

doi:10.3969/j.issn.2095-4344.2016.07.001

Abstract

Abstract:

BACKGROUND: Fractures can induce bone cell hypoxia, and remarkably reduce the oxygen tension in cells. Hypoxia-inducible factor-2α is a key oxygen-dependent transcriptional activator to regulate the body function under hypoxia and mediate the release of various inflammatory factors after fractures.
OBJECTIVE: To explore the role of Laquinimod in expression and function of hypoxia-inducible factor-2α in osteoblasts.
METHODS: Mouse osteoblasts MC3T3-E1 (clone 14) were pretreated with Laquinimod at various concentrations(10-100 μmol/L) before hypoxia in the presence or absence of specific proteasome inhibitors MG132 or N-acetyl-leucyl-leucyl-norleucine. Then, the media were pre-conditioned in 1% or 21% oxygen tension for 1 to 24 hours.
RESULTS AND CONCLUSION: Under hypoxia, the expression of hypoxia-inducible factor-2α in osteoblasts was increased remarkably, and Laquinimod could inhibit the expression of hypoxia-inducible factor-2α and its target genes in mouse MC3T3-E1 cells. Mechanistically, Laquinimod promoted hypoxia-inducible factor-2α degradation in a proteasome-dependent but von Hippel-Lindau protein-independent manner. Importantly, we found that Laquinimod disrupted the interaction between hypoxia-inducible factor-2α and its chaperone heat shock protein 90, but promoted the interaction between hypoxia-inducible factor-2α and the receptor of activated protein kinase C. These findings suggest that Laquinimod may promote the degradation of hypoxia-inducible factor-2α by affecting its folding and maturation. Laquinimod is a novel inhibitor of hypoxia-inducible factor-2α by changing its functional interaction with chaperone proteins heat shock protein 90 and receptor of activated protein kinase C.

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

Zhao Guang-zong, Fang Jun, Ding Gang, Zhang Long-qiang, Li Hua-zhuang, Gao Ke-hai. Laquinimod inhibits the expression and function of hypoxia-inducible factor-2 alpha in osteoblasts[J]. Chinese Journal of Tissue Engineering Research, 2016, 20(7): 917-924.

Figures/Tables 3

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