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 peroxiclase-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. (C) 2004 Elsevier Inc. All rights reserved.