title: Antioxidant alpha-lipoic acid inhibits osteoclast differentiation by reducing nuclear factor-kappaB DNA binding and prevents in vivo bone resorption induced by receptor activator of nuclear factor-kappaB ligand and tumor necrosis factor-alpha.
abstract: The relationship between oxidative stress and bone mineral density or osteoporosis has recently been reported. As bone loss occurring in osteoporosis and inflammatory diseases is primarily due to increases in osteoclast number, reactive oxygen species (ROS) may be relevant to osteoclast differentiation, which requires receptor activator of nuclear factor-kappaB ligand (RANKL). Tumor necrosis factor-alpha (TNF-alpha) frequently present in inflammatory conditions has a profound synergy with RANKL in osteoclastogenesis. In this study, we investigated the effects of alpha-lipoic acid (alpha-LA), a strong antioxidant clinically used for some time, on osteoclast differentiation and bone resorption. At concentrations showing no growth inhibition, alpha-LA potently suppressed osteoclastogenesis from bone marrow-derived precursor cells driven either by a high-dose RANKL alone or by a low-dose RANKL plus TNF-alpha (RANKL/TNF-alpha). alpha-LA abolished ROS elevation by RANKL or RANKL/TNF-alpha and inhibited NF-kappaB activation in osteoclast precursor cells. Specifically, alpha-LA reduced DNA binding of NF-kappaB but did not inhibit IKK activation. Furthermore, alpha-LA greatly suppressed in vivo bone loss induced by RANKL or TNF-alpha in a calvarial remodeling model. Therefore, our data provide evidence that ROS plays an important role in osteoclast differentiation through NF-kappaB regulation and the antioxidant alpha-lipoic acid has a therapeutic potential for bone erosive diseases.
authors.affiliation: Department of Cell and Developmental Biology, Brain Korea 21 Program, and Dental Research Institute, Seoul National University School of Dentistry, 28 Yeongon-Dong, Chongno-Gu, Seoul 110-749, Korea.
authors.forename: Hyon Jong
authors.initials: HJ
authors.lastname: Kim
authors.forename: Eun-Ju
authors.initials: EJ
authors.lastname: Chang
authors.forename: Hyun-Man
authors.initials: HM
authors.lastname: Kim
authors.forename: Seung Bok
authors.initials: SB
authors.lastname: Lee
authors.forename: Hyun-Duck
authors.initials: HD
authors.lastname: Kim
authors.forename: Ghi
authors.initials: G
authors.lastname: Su Kim
authors.forename: Hong-Hee
authors.initials: HH
authors.lastname: Kim
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D015153:Blotting, Western; D001862:Bone Resorption / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects*; D024202:Electrophoretic Mobility Shift Assay; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D018613:Microscopy, Confocal; D016328:NF-kappa B; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects*; D053245:RANK Ligand; D017382:Reactive Oxygen Species; D053246:Receptor Activator of Nuclear Factor-kappa B; D020133:Reverse Transcriptase Polymerase Chain Reaction; D008063:Thioctic Acid / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000975:Antioxidants; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D053245:RANK Ligand; D017382:Reactive Oxygen Species; D053246:Receptor Activator of Nuclear Factor-kappa B; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D008063:Thioctic Acid