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Dehydrocostus lactone inhibits NFATc1 via regulation of IKK, JNK and Nrf2, thereby attenuating osteoclastogenesis
Hye In Lee1,#, Gong-Rak Lee1,#, Jiae Lee1, Narae Kim1, Minjeong Kwon1, Hyun Jin Kim1, Nam Young Kim1, Jin Ha Park1, Woojin Jeong1,*
1Department of Life Science, Ewha Womans University
Abstract
Excessive and hyperactive osteoclast activity causes bone diseases such as osteoporosis and periodontitis. Thus, the regulation of osteoclast differentiation has clinical implications. We recently reported that dehydrocostus lactone (DL) inhibits osteoclast differentiation by regulating nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), but the underlying mechanism remains to be elucidated. Here, we demonstrated that DL inhibits NFATc1 by regulating nuclear factor-リB (NF-リB), activator protein-1 (AP-1) and nuclear factor-erythroid 2-related factor 2 (Nrf2). DL attenuated IリBメ phosphorylation and p65 nuclear translocation as well as decreased the expression of NF-リB target genes and c-Fos. It also inhibited c-Jun N-terminal kinase (JNK) but not p38 or extracellular signal-regulated kinase. The reporter assay revealed that DL inhibits NF-リB and AP-1 activation. In addition, DL reduced reactive oxygen species either by scavenging them or by activating Nrf2. The DL inhibition of NFATc1 expression and osteoclast differentiation was less effective in Nrf2-deficient cells. Collectively, these results suggest that DL regulates NFATc1 by inhibiting NF-リB and AP-1 via down-regulation of IリB kinase and JNK as well as by activating Nrf2, and thereby attenuates osteoclast differentiation.
Abstract, Accepted Manuscript(in press) [Submitted on August 28, 2019, Accepted on September 30, 2019]
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