Regulation of human osteoclast differentiation by thioredoxin binding protein-2 and redox-sensitive signaling.
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-kappaB 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-kappaB. 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.[1]References
- Regulation of human osteoclast differentiation by thioredoxin binding protein-2 and redox-sensitive signaling. Aitken, C.J., Hodge, J.M., Nishinaka, Y., Vaughan, T., Yodoi, J., Day, C.J., Morrison, N.A., Nicholson, G.C. J. Bone Miner. Res. (2004) [Pubmed]
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