Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
권호 표지
DOI QR코드

DOI QR Code

Silibinin Inhibits Osteoclast Differentiation Mediated by TNF Family Members

  • Kim, Jung Ha (National Research Laboratory for Regulation of Bone Metabolism and Disease, Department of Pharmacology, Brain Korea 21, Chonnam National University Medical School) ;
  • Kim, Kabsun (National Research Laboratory for Regulation of Bone Metabolism and Disease, Department of Pharmacology, Brain Korea 21, Chonnam National University Medical School) ;
  • Jin, Hye Mi (National Research Laboratory for Regulation of Bone Metabolism and Disease, Department of Pharmacology, Brain Korea 21, Chonnam National University Medical School) ;
  • Song, Insun (National Research Laboratory for Regulation of Bone Metabolism and Disease, Department of Pharmacology, Brain Korea 21, Chonnam National University Medical School) ;
  • Youn, Bang Ung (National Research Laboratory for Regulation of Bone Metabolism and Disease, Department of Pharmacology, Brain Korea 21, Chonnam National University Medical School) ;
  • Lee, Junwon (Department of Life Science and Genetic Engineering, Pai Chai University) ;
  • Kim, Nacksung (National Research Laboratory for Regulation of Bone Metabolism and Disease, Department of Pharmacology, Brain Korea 21, Chonnam National University Medical School)
  • Received : 2009.07.20
  • Accepted : 2009.07.30
  • Published : 2009.09.30
⟨ Previous Next ⟩

Abstract

Silibinin is a polyphenolic flavonoid compound isolated from milk thistle (Silybum marianum), with known hepatoprotective, anticarcinogenic, and antioxidant effects. Herein, we show that silibinin inhibits receptor activator of $NF-{\kappa}B$ ligand (RANKL)-induced osteoclastogenesis from RAW264.7 cells as well as from bone marrow-derived monocyte/macrophage cells in a dose-dependent manner. Silibinin has no effect on the expression of RANKL or the soluble RANKL decoy receptor osteoprotegerin (OPG) in osteoblasts. However, we demonstrate that silibinin can block the activation of $NF-{\kappa}B$, c-Jun N-terminal kinase (JNK), p38 mitogen-activated protein (MAP) kinase, and extracellular signal-regulated kinase (ERK) in osteoclast precursors in response to RANKL. Furthermore, silibinin attenuates the induction of nuclear factor of activated T cells (NFAT) c1 and osteoclast-associated receptor (OSCAR) expression during RANKL-induced osteoclastogenesis. We demonstrate that silibinin can inhibit $TNF-{\alpha}$-induced osteoclastogenesis as well as the expression of NFATc1 and OSCAR. Taken together, our results indicate that silibinin has the potential to inhibit osteoclast formation by attenuating the downstream signaling cascades associated with RANKL and $TNF-{\alpha}$.

Keywords

Acknowledgement

Supported by : Korea Science and Engineering Foundation, Chonnam National University

References

  1. Boyle, W.J., Simonet, W.S., and Lacey, D.L. (2003). Osteoclast differentiation and activation. Nature 423, 337-342 https://doi.org/10.1038/nature01658
  2. Hahn, G., Lehmann, H.D., Kurten, M., Uebel, H., and Vogel, G. (1968). [On the pharmacology and toxicology of silymarin, an antihepatotoxic active principle from Silybum marianum (L.) Gaertn]. Arzneimittel-Forschung 18, 698-704
  3. Hsu, H., Lacey, D.L., Dunstan, C.R., Solovyev, I., Colombero, A., Timms, E., Tan, H.L., Elliott, G., Kelley, M.J., Sarosi, I.I et al. (1999). Tumor necrosis factor receptor family member RANK mediates osteoclast differentiation and activation induced by osteoprotegerin ligand. Proc. Natl. Acad. Sci. USA 96, 3540-3545 https://doi.org/10.1073/pnas.96.7.3540
  4. Kim, N., Takami, M., Rho, J., Josien, R., and Choi, Y. (2002). A novel member of the leukocyte receptor complex regulates osteoclast differentiation. J. Exp. Med. 195, 201-209 https://doi.org/10.1084/jem.20011681
  5. Kim, K., Kim, J.H., Lee, J., Jin, H.M., Lee, S.H., Fisher, D.E., Kook, H., Kim, K.K., Choi, Y., and Kim, N. (2005a). Nuclear factor of activated T cells c1 induces osteoclast-associated receptor gene expression during tumor necrosis factor-related activationinduced cytokine-mediated osteoclastogenesis. J. Biol. Chem. 280, 35209-35216 https://doi.org/10.1074/jbc.M505815200
  6. Kim, N., Kadono, Y., Takami, M., Lee, J., Lee, S.H., Okada, F., Kim, J.H., Kobayashi, T., Odgren, P.R., Nakano, H., et al. (2005b). Osteoclast differentiation independent of the TRANCE-RANKTRAF6 axis. J. Exp. Med. 202, 589-595 https://doi.org/10.1084/jem.20050978
  7. Kim, K., Kim, J.H., Lee, J., Jin, H.M., Kook, H., Kim, K.K., Lee, S.Y., and Kim, N. (2007). MafB negatively regulates RANKL-mediated osteoclast differentiation. Blood 109, 3253-3259 https://doi.org/10.1182/blood-2006-09-048249
  8. Kim, K., Lee, S.H., Ha Kim, J., Choi, Y., and Kim, N. (2008). NFATc1 induces osteoclast fusion via up-regulation of Atp6v0d2 and the dendritic cell-specific transmembrane protein (DCSTAMP). Mol. Endocrinol. (Baltimore, Md.) 22, 176-185 https://doi.org/10.1210/me.2007-0237
  9. Kobayashi, K., Takahashi, N., Jimi, E., Udagawa, N., Takami, M., Kotake, S., Nakagawa, N., Kinosaki, M., Yamaguchi, K., Shima, N., et al. (2000). Tumor necrosis factor alpha stimulates osteoclast differentiation by a mechanism independent of the ODF/ RANKL-RANK interaction. J. Exp. Med. 191, 275-286 https://doi.org/10.1084/jem.191.2.275
  10. Koga, T., Inui, M., Inoue, K., Kim, S., Suematsu, A., Kobayashi, E., Iwata, T., Ohnishi, H., Matozaki, T., Kodama, T., et al. (2004). Costimulatory signals mediated by the ITAM motif cooperate with RANKL for bone homeostasis. Nature 428, 758-763 https://doi.org/10.1038/nature02444
  11. Kwak, H.B., Sun, H.M., Ha, H., Lee, J.H., Kim, H.N., and Lee, Z.H. (2008). AG490, a Jak2-specific inhibitor, induces osteoclast survival by activating the Akt and ERK signaling pathways. Mol. Cells 26, 436-442
  12. Lacey, D.L., Timms, E., Tan, H.L., Kelley, M.J., Dunstan, C.R., Burgess, T., Elliott, R., Colombero, A., Elliott, G., Scully, S., et al. (1998). Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 93, 165-176 https://doi.org/10.1016/S0092-8674(00)81569-X
  13. Lee, Z.H., and Kim, H.H. (2003). Signal transduction by receptor activator of nuclear factor kappa B in osteoclasts. Biochem. Biophys. Res. Comm. 305, 211-214 https://doi.org/10.1016/S0006-291X(03)00695-8
  14. Lee, S.E., Chung, W.J., Kwak, H.B., Chung, C.H., Kwack, K.B., Lee, Z.H., and Kim, H.H. (2001). Tumor necrosis factor-alpha supports the survival of osteoclasts through the activation of Akt and ERK. J. Biol. Chem. 276, 49343-49349 https://doi.org/10.1074/jbc.M103642200
  15. Lee, J., Kim, K., Kim, J.H., Jin, H.M., Choi, H.K., Lee, S.H., Kook, H., Kim, K.K., Yokota, Y., Lee, S.Y., et al. (2006). Id helix-loop-helix proteins negatively regulate TRANCE-mediated osteoclast differentiation. Blood 107, 2686-2693 https://doi.org/10.1182/blood-2005-07-2798
  16. Li, L.H., Wu, L.J., Tashiro, S.I., Onodera, S., Uchiumi, F., and Ikejima, T. (2006). The roles of Akt and MAPK family members in silymarin's protection against UV-induced A375-S2 cell apoptosis. Int. Immunopharmacol. 6, 190-197 https://doi.org/10.1016/j.intimp.2005.08.003
  17. Manna, S.K., Mukhopadhyay, A., Van, N.T., and Aggarwal, B.B. (1999). Silymarin suppresses TNF-induced activation of NFkappa B, c-Jun N-terminal kinase, and apoptosis. J. Immunol. 163, 6800-6809
  18. Ramasamy, K., and Agarwal, R. (2008). Multitargeted therapy of cancer by silymarin. Cancer Lett. 269, 352-362 https://doi.org/10.1016/j.canlet.2008.03.053
  19. Rho, J., Takami, M., and Choi, Y. (2004). Osteoimmunology: interactions of the immune and skeletal systems. Mol. Cells 17, 1-9
  20. Singh, R.P., and Agarwal, R. (2002). Flavonoid antioxidant silymarin and skin cancer. Antioxid. Redox Signal. 4, 655-663 https://doi.org/10.1089/15230860260220166
  21. Singh, R.P., and Agarwal, R. (2005). Mechanisms and preclinical efficacy of silibinin in preventing skin cancer. Eur. J. Cancer 41, 1969-1979 https://doi.org/10.1016/j.ejca.2005.03.033
  22. Singh, R.P., Dhanalakshmi, S., Tyagi, A.K., Chan, D.C., Agarwal, C., and Agarwal, R. (2002). Dietary feeding of silibinin inhibits advance human prostate carcinoma growth in athymic nude mice and increases plasma insulin-like growth factor-binding protein-3 levels. Cancer Res. 62, 3063-3069
  23. Singh, R.P., Dhanalakshmi, S., Agarwal, C., and Agarwal, R. (2005). Silibinin strongly inhibits growth and survival of human endothelial cells via cell cycle arrest and downregulation of survivin, Akt and NF-kappaB: implications for angioprevention and antiangiogenic therapy. Oncogene 24, 1188-1202 https://doi.org/10.1038/sj.onc.1208276
  24. Suda, T., Jimi, E., Nakamura, I., and Takahashi, N. (1997). Role of 1 alpha,25-dihydroxyvitamin D3 in osteoclast differentiation and function. Methods Enzymol. 282, 223-235 https://doi.org/10.1016/S0076-6879(97)82110-6
  25. Suda, T., Takahashi, N., Udagawa, N., Jimi, E., Gillespie, M.T., and Martin, T.J. (1999). Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr. Rev. 20, 345-357 https://doi.org/10.1210/er.20.3.345
  26. Takayanagi, H., Kim, S., Koga, T., Nishina, H., Isshiki, M., Yoshida, H., Saiura, A., Isobe, M., Yokochi, T., Inoue, J., et al. (2002). Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev. Cell 3, 889-901 https://doi.org/10.1016/S1534-5807(02)00369-6
  27. Walsh, M.C., Kim, N., Kadono, Y., Rho, J., Lee, S.Y., Lorenzo, J., and Choi, Y. (2006). Osteoimmunology: interplay between the immune system and bone metabolism. Ann. Rev. Immunol. 24, 33-63 https://doi.org/10.1146/annurev.immunol.24.021605.090646
  28. Yasuda, H., Shima, N., Nakagawa, N., Yamaguchi, K., Kinosaki, M., Mochizuki, S., Tomoyasu, A., Yano, K., Goto, M., Murakami, A., et al. (1998). Osteoclast differentiation factor is a ligand for osteoprotegerin/ osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc. Natl. Acad. Sci. USA 95, 3597-3602 https://doi.org/10.1073/pnas.95.7.3597

Cited by

  1. Pim-1 Regulates RANKL-Induced Osteoclastogenesis via NF-κB Activation and NFATc1 Induction vol.185, pp.12, 2009, https://doi.org/10.4049/jimmunol.1000885
  2. The Role of Osteoclast-Associated Receptor in Osteoimmunology vol.186, pp.1, 2011, https://doi.org/10.4049/jimmunol.1002483
  3. 몇 가지 주요 식용버섯의 생리기능성 물질 탐색과 파골세포 분화 저해물질의 생산 vol.40, pp.2, 2009, https://doi.org/10.4489/kjm.2012.40.2.114
  4. SLAT negatively regulates RANKL-induced osteoclast differentiation vol.36, pp.3, 2009, https://doi.org/10.1007/s10059-013-0159-x
  5. Mediators of Inflammation-Induced Bone Damage in Arthritis and Their Control by Herbal Products vol.2013, pp.None, 2009, https://doi.org/10.1155/2013/518094
  6. Silibinin Inhibits LPS-Induced Macrophage Activation by Blocking p38 MAPK in RAW 264.7 Cells vol.21, pp.4, 2009, https://doi.org/10.4062/biomolther.2013.044
  7. Acteoside Suppresses RANKL-Mediated Osteoclastogenesis by Inhibiting c-Fos Induction and NF-κB Pathway and Attenuating ROS Production vol.8, pp.12, 2013, https://doi.org/10.1371/journal.pone.0080873
  8. Silymarin Inhibits Morphological Changes in LPS-Stimulated Macrophages by Blocking NF-${\kappa}B$ Pathway vol.19, pp.3, 2009, https://doi.org/10.4196/kjpp.2015.19.3.211
  9. Molecular signaling mechanisms behind polyphenol-induced bone anabolism vol.16, pp.6, 2009, https://doi.org/10.1007/s11101-017-9529-x
  10. The Incorporation of Strontium to Improve Bone-Regeneration Ability of Mesoporous Bioactive Glasses vol.11, pp.5, 2018, https://doi.org/10.3390/ma11050678
  11. Dietary nutraceuticals as backbone for bone health vol.36, pp.6, 2018, https://doi.org/10.1016/j.biotechadv.2018.03.014
  12. Modulatory effects of silibinin in cell behavior during osteogenic phenotype vol.120, pp.8, 2009, https://doi.org/10.1002/jcb.28616
  13. Local administration with silymarin could increase osseointegration of hydroxyapatite-coated titanium implants in ovariectomized rats vol.34, pp.5, 2009, https://doi.org/10.1177/0885328219863290
  14. Potential Advantages of Bioactive Compounds Extracted From Traditional Chinese Medicine to Inhibit Bone Destructions in Rheumatoid Arthritis vol.11, pp.None, 2009, https://doi.org/10.3389/fphar.2020.561962
  15. Emerging Natural-Product-Based Treatments for the Management of Osteoarthritis vol.10, pp.2, 2009, https://doi.org/10.3390/antiox10020265