Dimethyl fumarate inhibits the expression and function of hypoxia-inducible factor-1α (HIF-1α)

Osteocyte hypoxia has been induced by skeletal unloading and fracture. Hypoxia-dependent regulation of gene expression is mediated by hypoxia-sensitive transcription factors such as hypoxia-inducible factor-1 alpha (HIF-1 alpha). Dimethyl fumarate (DMF) is a recently approved first-line therapy for multiple sclerosis. However, the role of DMF in regulating HIF-1 alpha expression and function has not been evaluated. In this study, we found that DMF inhibited hypoxia-induced expression of HIF-1 alpha and its target genes such as interleukin 8 (IL-8) and vascular endothelial growth factor (VEGF) in MC3T3 E1 cells. Mechanistically, DMF promoted HIF-1 alpha degradation in a proteasome-dependent but von Hippel-Lindau (VHL) protein-independent manner. Importantly, we found that DMF disrupted the interaction between HIF-1 alpha and its chaperone heat shock protein 90 (Hsp90) but promoted the interaction between HIF-1 alpha and the receptor of activated protein kinase C (RACK1). These data suggest that DMF might promote degradation of HIF-1 alpha by affecting its folding and maturation. Based on these observations, we conclude that DMF is a novel inhibitor of HIF-1 alpha. (C) 2014 Published by Elsevier Inc.