title: The inhibitory effect of beta-lapachone on RANKL-induced osteoclastogenesis.
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.
authors.affiliation: Department of Oral Microbiology and Immunology, College of Dentistry, Wonkwang University, Republic of Korea; Center for Metabolic Function Regulation (CMFR), School of Medicine, Wonkwang University, Republic of Korea.
authors.forename: Dong Ryun
authors.initials: DR
authors.lastname: Gu
authors.affiliation: Center for Metabolic Function Regulation (CMFR), School of Medicine, Wonkwang University, Republic of Korea.
authors.forename: Joon No
authors.initials: JN
authors.lastname: Lee
authors.affiliation: Center for Metabolic Function Regulation (CMFR), School of Medicine, Wonkwang University, Republic of Korea.
authors.forename: Gi-Su
authors.initials: GS
authors.lastname: Oh
authors.affiliation: Center for Metabolic Function Regulation (CMFR), School of Medicine, Wonkwang University, Republic of Korea.
authors.forename: Hyung Jin
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Department of Oral Physiology, College of Dentistry, Wonkwang University, Republic of Korea; Institute of Biomaterials Implant, Wonkwang University, Republic of Korea.
authors.forename: Min Seuk
authors.initials: MS
authors.lastname: Kim
authors.affiliation: Department of Oral Microbiology and Immunology, College of Dentistry, Wonkwang University, Republic of Korea; Center for Metabolic Function Regulation (CMFR), School of Medicine, Wonkwang University, Republic of Korea; Institute of Biomaterials Implant, Wonkwang University, Republic of Korea; Integrated Omics Institute, Wonkwang University, Iksan, Jeonbuk, 54538, Republic of Korea. Electronic address: leesh2@wku.ac.kr.
authors.forename: Seoung Hoon
authors.initials: SH
authors.lastname: Lee
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D001847:Bone Diseases / Q000378:metabolism; D002454:Cell Differentiation; D002470:Cell Survival; D020869:Gene Expression Profiling; D051379:Mice; D008810:Mice, Inbred C57BL; D009243:NAD / Q000737:chemistry; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D009285:Naphthoquinones / Q000737:chemistry*; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism; D010012:Osteogenesis; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D050778:NFATC Transcription Factors; D009285:Naphthoquinones; C494005:Nfatc1 protein, mouse; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D016760:Proto-Oncogene Proteins c-fos; D053245:RANK Ligand; C505689:Tnfsf11 protein, mouse; D009243:NAD; C014638:beta-lapachone; D016660:NAD(P)H Dehydrogenase (Quinone); C491732:Nqo1 protein, mouse; D055372:AMP-Activated Protein Kinases
keywords: Osteoclast; Osteoclastogenesis; Osteoporosis; PGC1β; PPARγ; β-Lapachone