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Author Gu, Dong Ryun ♦ Lee, Joon No ♦ Oh, Gi-Su ♦ Kim, Hyung Jin ♦ Kim, Min Seuk ♦ Lee, Seoung Hoon
Source United States Department of Energy Office of Scientific and Technical Information
Content type Text
Language English
Subject Keyword APPLIED LIFE SCIENCES ♦ ACID PHOSPHATASE ♦ BINDING ENERGY ♦ INHIBITION ♦ METABOLIC DISEASES ♦ RECEPTORS ♦ RHEUMATIC DISEASES ♦ TRANSCRIPTION FACTORS
Abstract 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. - Highlights: • 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.
ISSN 0006291X
Educational Use Research
Learning Resource Type Article
Publisher Date 2017-01-22
Publisher Place United States
Journal Biochemical and Biophysical Research Communications
Volume Number 482
Issue Number 4


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