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Cyclolinopeptide F, a cyclic peptide from flaxseed inhibited RANKL-induced osteoclastogenesis via downergulation of RANK expression

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Abstract

Previously, we reported that cyclolinopeptides (CLs) extracted from flaxseed inhibited receptor activator of nuclear factor κ-B ligand (RANKL)-induced osteoclastogenesis from mouse bone marrow cells in vitro. However, mode of action involved in CLs-inhibited osteoclastogenesis has been yet unknown. Therefore, in this study, we investigated the details of inhibitory activity of cyclolinopeptide-F (CL-F) in osteoclastogenesis, as a representative of CLs. CL-F dose-dependently inhibited RANKL-induced osteoclastogenesis (IC50 0.58 µM) without cytotoxic effects. The inhibition by CL-F was mainly observed in macrophage colony-stimulating factor (M-CSF)-induced proliferation/differentiation phase from M-CSF responsive immature myeloid cells to monocyte/macrophage (M/Mϕ) lineage. Additionally, CL-F also slightly inhibited RANKL-induced differentiation phase from M/Mϕ to mature osteoclasts. Expression of RANKL receptor, RANK, in M-CSF-induced M/Mϕ, i.e. osteoclast progenitor cells, was decreased by CL-F treatment. Furthermore, RT-PCR analysis revealed that CL-F inhibited c-fos gene expression, which is reported to be crucial for RANK expression in osteoclast progenitor cells induced with M-CSF from myeloid lineage cells. These results suggested that CL-F inhibits osteoclastogenesis via down regulation of c-fos expression, which leads to the down-regulation of RANK expression in M-CSF-induced osteoclast progenitors.

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Acknowledgement

This work was partly supported by a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan.

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  1. Toshio Kaneda and Yuki Nakajima contributed equally to this work.

Authors and Affiliations

  1. Faculty of Pharmaceutical Sciences, Hoshi University, Ebara 2-4-41 Shinagawa-ku, Tokyo, 142-8501, Japan

    Toshio Kaneda, Yuki Nakajima, Sae Koshikawa, Alfarius Eko Nugroho & Hiroshi Morita

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  1. Toshio Kaneda
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  2. Yuki Nakajima
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  3. Sae Koshikawa
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  4. Alfarius Eko Nugroho
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  5. Hiroshi Morita
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Correspondence to Hiroshi Morita.

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Kaneda, T., Nakajima, Y., Koshikawa, S. et al. Cyclolinopeptide F, a cyclic peptide from flaxseed inhibited RANKL-induced osteoclastogenesis via downergulation of RANK expression. J Nat Med 73, 504–512 (2019). https://doi.org/10.1007/s11418-019-01292-w

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  • DOI: https://doi.org/10.1007/s11418-019-01292-w

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