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Regulation of Human Osteoclast Differentiation by Thioredoxin Binding Protein‐2 and Redox‐Sensitive Signaling
Author(s) -
Aitken Cathy J,
Hodge Jason M,
Nishinaka Yumiko,
Vaughan Tanya,
Yodoi Junji,
Day Christopher J,
Morrison Nigel A,
Nicholson Geoffrey C
Publication year - 2004
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1359/jbmr.040913
Subject(s) - osteoclast , rankl , chemistry , activator (genetics) , signal transduction , microbiology and biotechnology , thioredoxin , transcription factor , cellular differentiation , biology , biochemistry , oxidative stress , receptor , gene
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.