Regulation of human osteoclast differentiation by thioredoxin binding protein-2 and redox-sensitive signaling

Aitken, Cathy J., Hodge, Jason M., Nishinaka, Yumiko, Vaughan, Tanya, Yodoi, Junji, Day, Christopher J., Morrison, Nigel A . and Nicholson, Geoffrey C. (2004) Regulation of human osteoclast differentiation by thioredoxin binding protein-2 and redox-sensitive signaling. Journal of Bone and Mineral Research, 19 12: 2057-2064. doi:10.1359/JBMR.040913

Author Aitken, Cathy J.
Hodge, Jason M.
Nishinaka, Yumiko
Vaughan, Tanya
Yodoi, Junji
Day, Christopher J.
Morrison, Nigel A .
Nicholson, Geoffrey C.
Title Regulation of human osteoclast differentiation by thioredoxin binding protein-2 and redox-sensitive signaling
Journal name Journal of Bone and Mineral Research   Check publisher's open access policy
ISSN 0884-0431
Publication date 2004-12
Sub-type Article (original research)
DOI 10.1359/JBMR.040913
Volume 19
Issue 12
Start page 2057
End page 2064
Total pages 8
Place of publication Malden, MA, United States
Publisher Wiley-Blackwell
Language eng
Formatted abstract
Differential expression of TBP-2 and Trx-1 occurs during osteoclastogenesis. Adenoviral overexpression of TBP-2 in osteoclast precursors inhibits Trx-1 expression, osteoclast formation, and AP-1 binding activity. TBP-2 and Trx-1 are key regulators of osteoclastogenesis. Introduction: Thioredoxin binding protein-2 (TBP-2) negatively regulates thioredoxin-1 (Trx-1), a key endogenous modulator of cellular redox and signaling. In gene array analysis, we found that TBP-2 expression was reduced during human osteoclast differentiation compared with macrophage differentiation. Our aim was to determine the roles of TBP-2 and Trx-1 in human osteoclastogenesis and RANKL signaling. Materials and Methods: Osteoclasts or macrophages were generated from colony-forming unit-granulocyte macrophage (CFU-GM) precursors treated with sRANKL and macrophage-colony-stimulating factor (M-CSF), or M-CSF alone, respectively. Expression of TBP-2 and Trx-1 was quantified by real-time PCR and Western analysis. Adenoviral gene transfer was used to overexpress TBP-2 in precursors. NF-κB and activator protein 1 (AP-1) signaling was assessed with EMSA. Results: In the presence of sRANKL, expression of TBP-2 was decreased, whereas Trx-1 expression was increased. The antioxidant N-acetylcysteine reversed this pattern and markedly inhibited osteoclastogenesis. Adenoviral overexpression of human TBP-2 in precursors inhibited osteoclastogenesis and Trx-1 expression, inhibited sRANKL-induced DNA binding of AP-1, but enhanced sRANKL-induced DNA binding of NF-κB. Conclusions: These data support significant roles for TBP-2 and the Trx system in osteoclast differentiation that are mediated by redox regulation of AP-1 transcription. A likely mechanism of stress signal induction of bone resorption is provided. Modulators of the Trx system such as antioxidants have potential as antiresorptive therapies.
Keyword Osteoclast
Thioredoxin binding protein-2
Activator protein 1
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
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Citation counts: TR Web of Science Citation Count  Cited 22 times in Thomson Reuters Web of Science Article | Citations
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