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http://dx.doi.org/10.1007/s10059-009-0123-y

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)
Publication Information
Molecules and Cells / v.28, no.3, 2009 , pp. 201-207 More about this Journal
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
gene regulation; osteoclast differentiation; RANKL; Silibinin; TNF;
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Times Cited By KSCI : 2  (Citation Analysis)
Times Cited By Web Of Science : 5  (Related Records In Web of Science)
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1 Boyle, W.J., Simonet, W.S., and Lacey, D.L. (2003). Osteoclast differentiation and activation. Nature 423, 337-342   DOI   ScienceOn
2 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   DOI   ScienceOn
3 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   DOI   ScienceOn
4 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   DOI   ScienceOn
5 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   DOI   ScienceOn
6 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
7 Singh, R.P., and Agarwal, R. (2002). Flavonoid antioxidant silymarin and skin cancer. Antioxid. Redox Signal. 4, 655-663   DOI   ScienceOn
8 Singh, R.P., and Agarwal, R. (2005). Mechanisms and preclinical efficacy of silibinin in preventing skin cancer. Eur. J. Cancer 41, 1969-1979   DOI   ScienceOn
9 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   DOI   ScienceOn
10 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   DOI   ScienceOn
11 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   DOI   PUBMED
12 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   DOI   PUBMED
13 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   PUBMED
14 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   DOI   ScienceOn
15 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   DOI   ScienceOn
16 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   DOI   PUBMED
17 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   DOI   ScienceOn
18 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   DOI   ScienceOn
19 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   DOI   ScienceOn
20 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   DOI   ScienceOn
21 Ramasamy, K., and Agarwal, R. (2008). Multitargeted therapy of cancer by silymarin. Cancer Lett. 269, 352-362   DOI   ScienceOn
22 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   DOI   ScienceOn
23 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   PUBMED
24 Rho, J., Takami, M., and Choi, Y. (2004). Osteoimmunology: interactions of the immune and skeletal systems. Mol. Cells 17, 1-9   PUBMED
25 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   DOI   ScienceOn
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   DOI   ScienceOn
27 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   PUBMED
28 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   DOI   ScienceOn