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F4/80 inhibits osteoclast differentiation via downregulation of nuclear factor of activated T cells, cytoplasmic 1

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Abstract

Osteoclastogenesis is an essential process in bone metabolism, which can be induced by RANKL stimulation. The F4/80 glycoprotein is a member of the EGF-transmembrane 7 (TM7) family and has been established as a specific cell-surface marker for murine macrophages. This study aimed to identify the role of F4/80 in osteoclastogenesis. Using mouse bone marrow-derived macrophages (BMMs), we observed that the mRNA level of F4/80 was dramatically reduced as these cells differentiated into osteoclasts. Furthermore, osteoclastogenesis was decreased in F4/80high BMMs compared to F4/80−/low BMMs. The inhibitory effect of F4/80 was associated with decreased expression of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1). Ectopic overexpression of a constitutively active form of NFATc1 rescued the anti-osteoclastogenic effect of F4/80 completely, suggesting that the anti-osteoclastogenic effect of F4/80 was mainly due to reduction in NFATc1 expression. As an underlying mechanism, we demonstrated that the presence of F4/80 abrogated the effect of RANKL on the phosphorylation of CREB and activated the expression of IFN-β, which are restored by cyclic AMP. Collectively, our results demonstrate that the presence of F4/80 suppresses RANKL-induced osteoclastogenesis by impairing the expression of NFATc1 via CREB and IFN-β. Therefore, F4/80 may hold therapeutic potential for bone destructive diseases.

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Acknowledgments

This work was supported by Grants from the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea (HI14C24470000) and from the National Research Foundation of Korea (NRF), funded by Ministry of Science, ICT and Future Planning (MSIP) (NRF-2014M1A3A3A02034917).

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    1. College of Pharmacy, Sookmyung Women’s University, Seoul, 140-742, Republic of Korea

      Ju-Hee Kang, Jung-Sun Sim, Ting Zheng & Mijung Yim

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    1. Ju-Hee Kang
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    2. Jung-Sun Sim
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    3. Ting Zheng
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    Correspondence to Mijung Yim.

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    Ju-Hee Kang and Jung-Sun Sim have contributed equally to this work.

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    Kang, JH., Sim, JS., Zheng, T. et al. F4/80 inhibits osteoclast differentiation via downregulation of nuclear factor of activated T cells, cytoplasmic 1. Arch. Pharm. Res. 40, 492–499 (2017). https://doi.org/10.1007/s12272-017-0900-7

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