Flunarizine inhibits osteoclastogenesis by regulating calcium signaling and promotes osteogenesis

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 implicati...

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Bibliographic Details
Published in:Journal of cellular physiology 2021-12, Vol.236 (12), p.8239-8252
Main Authors: Kim, Hyun Jin, Lee, Jiae, Lee, Gong‐Rak, Kim, Narae, Lee, Hye In, Kwon, Minjeong, Kim, Nam Young, Park, Jin Ha, Kang, Ye Hee, Song, Hyeong Ju, Kim, TaeSoo, Shin, Dong Min, Jeong, Woojin
Format: Article
Language:English
Subjects:
Animal models
Animals
Apoptosis
Biomedical materials
Bone diseases
Bone resorption
Bone Resorption - drug therapy
Bone Resorption - metabolism
Ca2+/calmodulin-dependent protein kinase IV
Calcineurin
Calcineurin - metabolism
Calcium
Calcium antagonists
Calcium ions
Calcium Signaling - drug effects
Calcium signalling
Calcium-binding protein
Calmodulin
Cell Differentiation - drug effects
Differentiation
Ectopic expression
flunarizine
Flunarizine - antagonists & inhibitors
Flunarizine - metabolism
Humans
Ionomycin
Kinases
Lipopolysaccharides
Lymphocytes
NF-AT protein
NFATC Transcription Factors - drug effects
NFATC Transcription Factors - metabolism
Nuclear transport
osteoblast
osteoclast
Osteoclastogenesis
Osteoclasts
Osteoclasts - drug effects
Osteoclasts - metabolism
Osteogenesis
Osteogenesis - drug effects
Osteogenesis - physiology
Osteoporosis
Osteoporosis - drug therapy
Osteoporosis - metabolism
Ovariectomy
Periodontitis
Post-menopause
Proteins
RANK Ligand - metabolism
Signaling
Transcription factors
Translocation
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Summary: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. Flunarizine (FN) inhibits osteoclastogenesis via regulating calmodulin‐dependent protein kinase IV and calcineurin as a calcium channel blocker. FN promotes osteoclast apoptosis and osteogenesis. FN protects bone destruction in mouse models of bone diseases induced by inflammation and ovariectomy.
ISSN:0021-9541
1097-4652
DOI:10.1002/jcp.30496