Flunarizine inhibits osteoclastogenesis by regulating calcium signaling and promotes osteogenesis

Hyun Jin Kim, Jiae Lee, Gong Rak Lee, Narae Kim, Hye In Lee, Minjeong Kwon, Nam Young Kim, Jin Ha Park, Ye Hee Kang, Hyeong Ju Song, Tae Soo Kim, Dong Min Shin, Woojin Jeong

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)8239-8252
Number of pages14
JournalJournal of Cellular Physiology
Volume236
Issue number12
DOIs
StatePublished - Dec 2021

Keywords

  • apoptosis
  • calcium
  • flunarizine
  • osteoblast
  • osteoclast

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