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

Cell Communication and Signaling - Tập 11 Số 1 - Trang 1-12 - 2013
Park, Kwang Hwan1,2,3,4, Park, Boryung5, Yoon, Dong Suk2, Kwon, Seung-Hyun1, Shin, Dong Min5, Lee, Jin Woo2, Lee, Hyun Gyu1, Shim, Jae-Hyuck4, Park, Jeon Han1,3, Lee, Jae Myun1,3
1Department of Microbiology, Yonsei University College of Medicine, Seoul, Republic of Korea
2Department of Orthopaedic Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea
3Brain Korea 21 Plus Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea
4Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, USA
5Department of Oral Biology, Yonsei University College of Dentistry, Seoul, Republic of Korea

Tóm tắt

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. 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. 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.

Tài liệu tham khảo

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