Laquinimod inhibits the expression and function of hypoxia-inducible factor-2 alpha in osteoblasts
10.3969/j.issn.2095-4344.2016.07.001
- VernacularTitle:拉喹莫德抑制成骨细胞中缺氧诱导因子2α的表达及其功能
- Author:
Guangzong ZHAO
;
Jun FANG
;
Gang DING
;
Longqiang ZHANG
;
Huazhuang LI
;
Kehai GAO
- Publication Type:Journal Article
- From:
Chinese Journal of Tissue Engineering Research
2016;20(7):917-924
- CountryChina
- Language:Chinese
-
Abstract:
BACKGROUND:Fractures can induce bone cel hypoxia, and remarkably reduce the oxygen tension in cels. 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-2αin osteoblasts.
METHODS: Mouse osteoblasts MC3T3-E1 (clone 14) were pretreated with Laquinimod at various concentrations(10-100μmol/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 cels. Mechanisticaly, 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.
