Thioredoxin-1 mediates osteoclast stimulation by reactive oxygen species.
We found that the antioxidant protein thioredoxin-1 (Trx) is more highly expressed in osteoclasts than in macrophages. Moreover, transfection of RAW 264.7 (RAW) cells with a Trx-expression construct resulted in a dramatic increase in their capacity for osteoclast formation. In contrast, Trx-expression was suppressed and osteoclast formation was abrogated by transfection with the antioxidant proteins glutathione peroxidase-1 (Gpx) or peroxiredoxin-1 (Prx). These divergent effects suggest that Trx augments osteoclast formation through some special function. It is known that Trx enhances the binding of several transcription factors to DNA. We found that AP-1, NFkappaB, and NFAT-reporter gene expression was enhanced more greatly by RANKL in RAW cells transfected with the Trx-expression construct. Thus, oxidants stimulate osteoclastic differentiation by induction of Trx-expression, which augments the DNA binding of transcription factors essential for osteoclastic differentiation. Conversely, antioxidants, including Gpx and Prx, suppress Trx-expression and thereby osteoclastic differentiation.
Lean
Jennifer
J
Department of Cellular Pathology, St. George's Hospital Medical School, Cranmer Terrace, London SW17 0RE, UK.
Kirstein
Barrie
B
Urry
Zoë
Z
Chambers
Timothy
T
Fuller
Karen
K
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001862:Bone Resorption / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D005979:Glutathione Peroxidase / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000494:pharmacology; D051379:Mice; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010544:Peroxidases / Q000235:genetics / Q000378:metabolism; D054464:Peroxiredoxins; D053245:RANK Ligand; D017382:Reactive Oxygen Species / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D013879:Thioredoxins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection
D000975:Antioxidants; D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D017382:Reactive Oxygen Species; D053246:Receptor Activator of Nuclear Factor-kappa B; D011994:Recombinant Proteins; C505686:TNFRSF11A protein, human; C505688:TNFSF11 protein, human; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D014157:Transcription Factors; D013879:Thioredoxins; D010544:Peroxidases; C515940:PRDX1 protein, human; D054464:Peroxiredoxins; D005979:Glutathione Peroxidase