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Zinc inhibits osteoclast differentiation by suppression of Ca2+-Calcineurin-NFATc1 signaling pathway

 Kwang Hwan Park  ;  Boryung Park  ;  Dong Suk Yoon  ;  Seung-Hyun Kwon  ;  Dong Min Shin  ;  Jin Woo Lee  ;  Hyun Gyu Lee  ;  Jae-Hyuck Shim  ;  Jeon Han Park  ;  Jae Myun Lee 
 Cell Communication and Signaling, Vol.11(1) : 74, 2013 
Journal Title
 Cell Communication and Signaling 
Issue Date
Animals ; Bone Marrow Cells/cytology ; Calcineurin/metabolism* ; Calcium/metabolism ; Cell Differentiation/drug effects ; Cell Line ; Cells, Cultured ; Mice ; Monocytes/drug effects* ; Monocytes/metabolism ; NFATC Transcription Factors/genetics ; NFATC Transcription Factors/metabolism* ; Osteoclasts/cytology ; Osteoclasts/drug effects* ; RANK Ligand/metabolism ; Signal Transduction/drug effects ; Zinc/pharmacology*
Zinc ; Bone loss ; Osteoclast ; NFATc1 ; Calcineurin ; Ca2+ oscillation
BACKGROUND: Zinc, an essential trace element, inhibits osteoclast differentiation in vitro and in vivo. The molecular mechanism for the inhibitory effect of zinc, however, is poorly understood. The purpose of this study was to investigate the effect of zinc and determine its molecular mechanism on receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis in mouse bone marrow-derived monocyte cells (BMMs) and RAW264.7 cells. RESULTS: In BMMs, zinc treatment during osteoclast differentiation decreased RANKL-induced osteoclast formation in a dose-dependent manner. We show that zinc suppressed the mRNA levels of nuclear factor of activated T-cells, cytoplasmic 1 (Nfatc1). Zinc also accumulated phospho-Nfatc1 (p-Nfatc1) in the cytosol in a dose-dependent manner and inhibited the translocation of Nfatc1 to the nucleus in RAW264.7 cells. Zinc suppressed the activities of Nfatc1 in the nucleus without changing the activities of NF-κB in RAW264.7 cells. In contrast, calcineurin activity decreased in response to zinc but its protein level was unchanged. RANKL-induced Ca2+ oscillations were inhibited by zinc treatment, but phospho-phospholipase Cγ1 (p-PLCγ1), the upstream signaling molecule of Ca2+ oscillations, was unaffected. Moreover, a constitutively active form of Nfatc1 obviously rescued suppression of osteoclastogenesis by zinc. CONCLUSIONS: Taken together, these results demonstrate for the first time that the inhibitory effect of zinc during osteoclastogesis is caused by suppressing the Ca2+-Calcineurin-NFATc1 signaling pathway. Thus, zinc may be a useful therapeutic candidate for the prevention of bone loss caused by NFATc1 activation in osteoclasts.
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Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Orthopedic Surgery (정형외과학교실) > 1. Journal Papers
2. College of Dentistry (치과대학) > Dept. of Oral Biology (구강생물학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Microbiology (미생물학교실) > 1. Journal Papers
Yonsei Authors
Park, Kwang Hwan(박광환) ORCID logo https://orcid.org/0000-0002-2110-0559
Park, Bo Ryung(박보령)
Park, Jeon Han(박전한) ORCID logo https://orcid.org/0000-0001-9604-3205
Shin, Dong Min(신동민) ORCID logo https://orcid.org/0000-0001-6042-0435
Lee, Jae Myun(이재면) ORCID logo https://orcid.org/0000-0002-5273-3113
Lee, Jin Woo(이진우) ORCID logo https://orcid.org/0000-0002-0293-9017
Lee, Hyun Gyu(이현규)
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