Advertisement

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

  • Toshio Kaneda
  • Yuki Nakajima
  • Sae Koshikawa
  • Alfarius Eko Nugroho
  • Hiroshi MoritaEmail author
Original Paper
  • 54 Downloads

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.

Keywords

Flaxseed Cyclic peptide Cyclolinopeptide Osteoclastogenesis Bone marrow macrophage Osteoclast 

Notes

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.

Supplementary material

11418_2019_1292_MOESM1_ESM.pdf (101 kb)
Supplementary material 1 (PDF 100 kb)

References

  1. 1.
    Shim YY, Gui B, Arnison PG, Wang Y, Reaney MJT (2014) Flaxseed (Linum usitatissimum L.) compositions and processing: a review. Trends Food Sci Technol 38:5–20CrossRefGoogle Scholar
  2. 2.
    Aladedunye F, Sosinska E, Przybylski R (2013) Flaxseed cyclolinopeptides: analysis and storage stability. J Am Oil Chem Soc 90:419–428CrossRefGoogle Scholar
  3. 3.
    Schmidt TJ, Klaes M, Sendker J (2012) Lignans in seeds of Linum species. J Phytochem 82:89–99CrossRefGoogle Scholar
  4. 4.
    Wang YF, Xu ZK, Yang DH, Yao HY, Ku BS, Ma XQ, Wang CZ, Liu SL, Cai SQ (2013) The antidepressant effect of secoisolariciresinol, a lignan-type phytoestrogen constituent of flaxseed, on ovariectomized mice. J Nat Med 67:222–227CrossRefPubMedGoogle Scholar
  5. 5.
    Kaufmann HP, Tobschirbel A (1959) An oligopeptide from linseed. Chem Ber 92:2805–2809CrossRefGoogle Scholar
  6. 6.
    Wieczorek Z, Bengtsson B, Trojnar J, Siemion IZ (1991) Immunosuppressive activity of cyclolinopeptide A. Pept Res 4:275–783PubMedGoogle Scholar
  7. 7.
    Kaneda T, Yoshida H, Nakajima Y, Toishi M, Nugroho Alfarius Eko, Morita H (2016) Cyclolinopeptides, cyclic peptides from flaxseed with osteoclast differentiation inhibitory activity. Bioorg Med Chem Lett 26:1760–1761CrossRefPubMedGoogle Scholar
  8. 8.
    Rodan GA, Martin TJ (2000) Therapeutic approaches to bone diseases. Science 289:1508–1514CrossRefPubMedGoogle Scholar
  9. 9.
    Loutit JF, Nisbet NW (1982) The origin of osteoclasts. Immunobiology 161:193–203CrossRefPubMedGoogle Scholar
  10. 10.
    Boyle WJ, Simonet WS, Lacey DL (2003) Osteoclast differentiation and activation. Nature 423:337–342CrossRefPubMedGoogle Scholar
  11. 11.
    Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, Morony S, Oliveira-dos-Santos AJ, Van G (1999) OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397:315–323CrossRefPubMedGoogle Scholar
  12. 12.
    Wiktor-Jedrzejczak W, Bartocci A, Ferrante AW Jr, Ahmed-Ansari A, Sell KW, Pollard JW, Stanley ER (1990) Total absence of colonystimulating factor 1 in the macrophage-deficient osteopetrotic (op/op) mouse. Proc Natl Acad Sci 87:4828–4832CrossRefPubMedGoogle Scholar
  13. 13.
    Yoshida H, Hayashi S, Kunisada T, Ogawa M, Nishikawa S, Okamura H, Sudo T, Shultz LD, Nishikawa S (1990) The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature 345:442–444CrossRefPubMedGoogle Scholar
  14. 14.
    Takayanagi H (2007) Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat Rev Immunol 7:292–304CrossRefPubMedGoogle Scholar
  15. 15.
    Arai A, Mizoguchi T, Harada S, Kobayashi Y, Nakamichi Y, Yasuda H, Penninger JM, Yamada K, Udagawa N, Takahashi N (2012) Fos plays an essential role in the upregulation of RANK expression in osteoclastprecursors within the bone microenvironment. J Cell Sci 125:2910–2917CrossRefPubMedGoogle Scholar
  16. 16.
    Kim JH, Kim N (2014) Regulation of NFATc1 in osteoclast differentiation. J Bone Metab 21:233–241CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Matsumoto T, Shishido A, Morita H, Itokawa H, Takeya K (2001) Cyclolinopeptides F-I, cyclic peptides from linseed. Phytochemistry 57:251–260CrossRefPubMedGoogle Scholar
  18. 18.
    Kaneda T, Nojima T, Nakagawa M, Ogasawara A, Kaneko H, Sato T, Mano H, Kumegawa M, Hakeda Y (2000) Endogenous production of TGF-beta is essential for osteoclastogenesis induced by a combination of receptor activator of NF-kappa B ligand and macrophage-colony-stimulating factor. J Immunol 165:4254–4263CrossRefPubMedGoogle Scholar
  19. 19.
    Hayashi T, Kaneda T, Toyama Y, Kumegawa M, Hakeda Y (2002) Regulation of receptor activator of NF-kappa B ligand-induced osteoclastogenesis by endogenous interferon-beta (INF-beta) and suppressors of cytokine signaling (SOCS). The possible counteracting role of SOCSs-in IFN-beta-inhibited osteoclast formation. J Biol Chem 277:27880–27886CrossRefPubMedGoogle Scholar
  20. 20.
    Janckila AJ, Takahashi K, Sun SZ, Yam LT (2001) Naphthol-ASBI phosphate as a preferred substrate for tartrate-resistant acid phosphatase isoform 5b. J Bone Miner Res 16:788–793CrossRefPubMedGoogle Scholar
  21. 21.
    Feng X, Teitelbaum SL (2013) Osteoclasts: new Insights. Bone Res 1:11–26CrossRefPubMedGoogle Scholar
  22. 22.
    Sherr CJ (1990) Colony-stimulating factor-1 receptor. Blood 75:1–12PubMedGoogle Scholar
  23. 23.
    Sato N, Sawada K, Kannonji M, Tarumi T, Sakai N, Ieko M, Sakurama S, Nakagawa S, Yasukouchi T, Krantz SB (1991) Purification of human marrow progenitor cells and demonstration of the direct action of macrophage colony-stimulating factor on colony-forming unit-macrophage. Blood 78:967–974PubMedGoogle Scholar
  24. 24.
    Wang ZQ, Ovitt C, Grigoriadis AE, Möhle-Steinlein U, Rüther U, Wagner EF (1992) Bone and haematopoietic defects in mice lacking c-fos. Nature 360:741–745CrossRefPubMedGoogle Scholar
  25. 25.
    Grigoriadis AE, Wang ZQ, Cecchini MG, Hofstetter W, Felix R, Fleisch HA, Wagner EF (1994) c-Fos: a key regulator of osteoclast-macrophage lineage determination and bone remodeling. Science 266:443–448CrossRefPubMedGoogle Scholar
  26. 26.
    Matsuo K, Owens JM, Tonko M, Elliott C, Chambers TJ, Wagner EF (2000) Fosl1 is a transcriptional target of c-Fos during osteoclast differentiation. Nat Genet 24:184–187CrossRefPubMedGoogle Scholar
  27. 27.
    Takayanagi H, Kim S, Matsuo K, Suzuki H, Suzuki T, Sato K, Yokochi T, Oda H, Nakamura K, Ida N, Wagner EF, Taniguchi T (2002) RANKL maintains bone homeostasis through c-Fos-dependent induction of interferon-beta. Nature 416:744–749CrossRefPubMedGoogle Scholar
  28. 28.
    Fleischmann A, Hafezi F, Elliott C, Remé CE, Rüther U, Wagner EF (2000) Fra-1 replaces c-Fos-dependent functions in mice. Genes Dev 14:2695–2700CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Hirsch S, Austyn JM, Gordon S (1981) Expression of the macrophage-specific antigen F4/80 during differentiation of mouse bone marrow cells in culture. J Exp Med 154:713–725CrossRefPubMedGoogle Scholar
  30. 30.
    Ma WJ, Cheng S, Campbell C, Wright A, Furneaux H (1996) Cloning and characterization of HuR, a ubiquitously expressed Elav-like protein. J Biol Chem 271:8144–8151CrossRefPubMedGoogle Scholar
  31. 31.
    Raghavan A, Robison RL, McNabb J, Miller CR, Williams DA, Bohjanen PR (2001) HuA and tristetraprolin are induced following T cell activation and display distinct but overlapping RNA binding specificities. J Biol Chem 276:47958–47965CrossRefPubMedGoogle Scholar
  32. 32.
    Glazier MG, Bowman MA (2001) A review of the evidence for the use of phytoestrogens as a replacement for traditional estrogen replacement therapy. Arch Intern Med 161:1161–1172CrossRefPubMedGoogle Scholar
  33. 33.
    Rietjens IMCM, Louisse J, Beekmann K (2017) The potential health effects of dietary phytoestrogens. Br J Pharmacol 174:1263–1280CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Society of Pharmacognosy 2019

Authors and Affiliations

  • Toshio Kaneda
    • 1
  • Yuki Nakajima
    • 1
  • Sae Koshikawa
    • 1
  • Alfarius Eko Nugroho
    • 1
  • Hiroshi Morita
    • 1
    Email author
  1. 1.Faculty of Pharmaceutical SciencesHoshi UniversityTokyoJapan

Personalised recommendations