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Flunarizine inhibits osteoclastogenesis by regulating calcium signaling and promotes osteogenesis.

Authors
  • Kim, Hyun Jin1
  • Lee, Jiae1
  • Lee, Gong-Rak1
  • Kim, Narae1
  • Lee, Hye In1
  • Kwon, Minjeong1
  • Kim, Nam Young1
  • Park, Jin Ha1
  • Kang, Ye Hee1
  • Song, Hyeong Ju1
  • Kim, TaeSoo1
  • Shin, Dong Min2
  • Jeong, Woojin1
  • 1 Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul, Korea. , (North Korea)
  • 2 Department of Oral Biology, Yonsei University College of Dentistry, Seoul, Korea. , (North Korea)
Type
Published Article
Journal
Journal of Cellular Physiology
Publisher
Wiley (John Wiley & Sons)
Publication Date
Dec 01, 2021
Volume
236
Issue
12
Pages
8239–8252
Identifiers
DOI: 10.1002/jcp.30496
PMID: 34192358
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Many bone diseases such as osteoporosis and periodontitis are caused by hyperactivation of osteoclasts. Calcium (Ca2+ ) signals are crucial for osteoclast differentiation and function. Thus, the blockade of Ca2+ signaling may be a strategy for regulating osteoclast activity and has clinical implications. Flunarizine (FN) is a Ca2+ channel antagonist that has been used for reducing migraines. However, the role of FN in osteoclast differentiation and function remains unknown. Here, we investigated whether FN regulates osteoclastogenesis and elucidated the molecular mechanism. FN inhibited osteoclast differentiation along with decreased expression of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), and attenuated osteoclast maturation and bone resorption. FN inhibition of osteoclast differentiation was restored by ectopic expression of constitutively active NFATc1. FN reduced calcium oscillations and its inhibition of osteoclast differentiation and resorption function was reversed by ionomycin, an ionophore that binds Ca2+ . FN also inhibited Ca2+ /calmodulin-dependent protein kinase IV (CaMKIV) and calcineurin leading to a decrease in the cAMP-responsive element-binding protein-dependent cFos and peroxisome proliferator-activated receptor-γ coactivator 1β expression, and NFATc1 nuclear translocation. These results indicate that FN inhibits osteoclastogenesis via regulating CaMKIV and calcineurin as a Ca2+ channel blocker. In addition, FN-induced apoptosis in osteoclasts and promoted osteogenesis. Furthermore, FN protected lipopolysaccharide- and ovariectomy-induced bone destruction in mouse models, suggesting that it has therapeutic potential for treating inflammatory bone diseases and postmenopausal osteoporosis. © 2021 Wiley Periodicals LLC.

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