HIF-1α stabilization in osteoclasts induces the expression of aerobic glycolysis-related proteins GLUT1, LDHA, and MCT4

Abstract

Hypoxia-inducible factor (HIF)-1α is a master transcription factor regulating hypoxic adaptation and activates the transcription of genes involved in various steps of energy metabolism. However, some subsets of cancer cells exhibit high HIF-1α levels regardless of the oxygen concentration. Even under normoxic and normoglycemic conditions, HIF-1α regulates basal expression of its target genes. Osteoclasts are giant multinucleated cells derived from the monocyte/macrophage lineage and are specialized in bone resorption. Excessive osteoclast resorbing activities is involved in destructive bone diseases. There are few data regarding how HIF-1α affects osteoclast differentiation. In this study, we investigated whether echinomycin, a HIF-1α inhibitor, reduced the expression of proteins of aerobic glycolysis, such as glucose transporter 1 (GLUT1), lactate dehydrogenase A (LDHA), and monocarboxylate transporter 4 (MCT4), and whether HIF-1α stabilization is involved in osteoclast differentiation. HIF-1α was stabilized earlier than the upregulation of GLUT1, LDHA, and MCT4 expression during osteoclast differentiation. Echinomycin inhibited GLUT1, LDHA, and MCT4 expression. It also inhibited osteoclast differentiation and suppressed osteoclast bone-resorbing activity. We propose that HIF-1α inhibition suppresses excessive osteoclast differentiation and may represent a novel therapeutic strategy for controlling excessive bone resorption in osteoporosis and rheumatoid arthritis.