The inhibitory effect of beta-lapachone on RANKL-induced osteoclastogenesis

• Published in: Biochemical and biophysical research communications 2017-01, Vol.482 (4), p.1073-1079
• Main Authors: Gu, Dong Ryun, Lee, Joon No, Oh, Gi-Su, Kim, Hyung Jin, Kim, Min Seuk, Lee, Seoung Hoon
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; ACID PHOSPHATASE; AMP-Activated Protein Kinases - metabolism; Animals; BINDING ENERGY; Bone Diseases - metabolism; Cell Differentiation; Cell Survival; Gene Expression Profiling; INHIBITION; METABOLIC DISEASES; Mice; Mice, Inbred C57BL; NAD - chemistry; NAD(P)H Dehydrogenase (Quinone) - metabolism; Naphthoquinones - chemistry; NFATC Transcription Factors - metabolism; Osteoclast; Osteoclastogenesis; Osteoclasts - cytology; Osteoclasts - metabolism; Osteogenesis; Osteoporosis; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism; PGC1β; PPARγ; Proto-Oncogene Proteins c-fos - metabolism; RANK Ligand - metabolism; Real-Time Polymerase Chain Reaction; RECEPTORS; RHEUMATIC DISEASES; TRANSCRIPTION FACTORS; β-Lapachone
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2016.11.160

β-lapachone (β-L) is a substrate of reduced nicotinamide adenine dinucleotide (NADH): quinone oxidoreductase 1 (NQO1). NQO1 reduces quinones to hydroquinones using NADH as an electron donor and consequently increases the intracellular NAD+/NADH ratio. The activation of NQO1 by β-L has beneficial effects on several metabolic syndromes, such as obesity, hypertension, and renal injury. However, the effect of β-L on bone metabolism remains unclear. Here, we show that β-L might be a potent inhibitor of receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis. β-L inhibited osteoclast formation in a dose-dependent manner and also reduced the expression of osteoclast differentiation marker genes, such as tartrate-resistant acid phosphatase (Acp5 or TRAP), cathepsin K (CtsK), the d2 isoform of vacuolar ATPase V0 domain (Atp6v0d2), osteoclast-associated receptor (Oscar), and dendritic cell-specific transmembrane protein (Dc-stamp). β-L treatment of RANKL-induced osteoclastogenesis significantly increased the cellular NAD+/NADH ratio and resulted in the activation of 5′ AMP-activated protein kinase (AMPK), a negative regulator of osteoclast differentiation. In addition, β-L treatment led to significant suppression of the expression of peroxisome proliferator-activated receptor gamma (PPARγ) and peroxisome proliferator-activated receptor gamma coactivator 1β (PGC1β), which can stimulate osteoclastogenesis. β-L treatment downregulated c-Fos and nuclear factor of activated T-cells 1 (NFATc1), which are master transcription factors for osteoclastogenesis. Taken together, the results demonstrated that β-L inhibits RANKL-induced osteoclastogenesis and could be considered a potent inhibitor of RANKL-mediated bone diseases, such as postmenopausal osteoporosis, rheumatoid arthritis, and periodontitis. •β-lapachone (β-L) inhibits RANKL-mediated osteoclastogenesis.•β-L increases the intracellular NAD+/NADH ratio, which is followed by activation of AMPK in osteoclasts.•The activation of AMPK by β-L inhibits c-Fos and NFATc1 expression in RANKL-induced osteoclastogenesis.•β-L also suppresses c-Fos and NFATc1 expression via downregulation of PPARγ and PGC1β expression.