Cinchonine inhibits osteoclast differentiation by regulating TAK1 and AKT, and promotes osteogenesis

You Jin Jo, Hye In Lee, Narae Kim, Donghyun Hwang, Jiae Lee, Gong Rak Lee, Seong Eun Hong, Hana Lee, Minjeong Kwon, Nam Young Kim, Hyun Jin Kim, Jin Ha Park, Ye Hee Kang, Han Sung Kim, Soo Young Lee, Woojin Jeong

Research output: Contribution to journalArticlepeer-review

9 Scopus citations

Abstract

Cinchonine (CN) has been known to exert antimalarial, antiplatelet, and antiobesity effects. It was also recently reported to inhibit transforming growth factor β-activated kinase 1 (TAK1) and protein kinase B (AKT) through binding to tumor necrosis factor receptor-associated factor 6 (TRAF6). However, its role in bone metabolism remains largely unknown. Here, we showed that CN inhibits osteoclast differentiation with decreased expression of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), a key determinant of osteoclastogenesis. Immunoblot and quantitative real-time polymerase chain reaction analysis as well as the reporter assay revealed that CN inhibits nuclear factor-κB and activator protein-1 by regulating TAK1. CN also attenuated the activation of AKT, cyclic AMP response element-binding protein, and peroxisome proliferator-activated receptor-γ coactivator 1β (PGC1β), an essential regulator of mitochondrial biogenesis. Collectively, these results suggested that CN may inhibit TRAF6-mediated TAK1 and AKT activation, which leads to downregulation of NFATc1 and PGC1β resulting in the suppression of osteoclast differentiation. Interestingly, CN not only inhibited the maturation and resorption function of differentiated osteoclasts but also promoted osteoblast differentiation. Furthermore, CN protected lipopolysaccharide- and ovariectomy-induced bone destruction in mouse models, suggesting its therapeutic potential for treating inflammation-induced bone diseases and postmenopausal osteoporosis.

Original languageEnglish
Pages (from-to)1854-1865
Number of pages12
JournalJournal of Cellular Physiology
Volume236
Issue number3
DOIs
StatePublished - Mar 2021

Keywords

  • AKT
  • TAK1
  • bone
  • cinchonine
  • osteoblast
  • osteoclast

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