Curcumin Inhibits Osteoclastogenesis by Decreasing Receptor Activator of Nuclear Factor-κB Ligand (RANKL) in Bone Marrow Stromal Cells

  • Oh, Sora (Department of Biological Sciences and Immunomodulation Research Center, University of Ulsan) ;
  • Kyung, Tae-Wook (Department of Biological Sciences and Immunomodulation Research Center, University of Ulsan) ;
  • Choi, Hye-Seon (Department of Biological Sciences and Immunomodulation Research Center, University of Ulsan)
  • Received : 2008.06.04
  • Accepted : 2008.07.28
  • Published : 2008.11.30

Abstract

Curcumin (diferuloylmethane), a pigment derived from turmeric, has anti-oxidant and anti-inflammatory activities. Accumulating evidence points to a biochemical link between increased oxidative stress and reduced bone density. Osteoclast formation was evaluated in co-cultures of bone marrow stromal cells (BMSC) and whole bone marrow cells (BMC). Expression of receptor activator of nuclear factor-${\kappa}B$ ligand (RANKL) was analyzed at the mRNA and protein levels. Exposure to curcumin led to dose-dependent suppression of osteoclastogenesis in the co-culture system, and to reduced expression of RANKL in $IL-1{\alpha}$-stimulated BMSCs. Addition of RANKL abolished the inhibition of osteoclastogenesis by curcumin, whereas the addition of prostaglandin $E_2$ ($PGE_2$) did not. The decreased osteoclastogenesis induced by curcumin may reduce bone loss and be of potential benefit in preventing and/or attenuating osteoporosis.

Keywords

Acknowledgement

Supported by : University of Ulsan

References

  1. Aggarwal, B.B., Kumar, A., and Bharti, A.C. (2003). Anticancer potential of curcumin: preclinical and clinical studies. Anticancer Res. 23, 363-398
  2. Bai, X., Lu, D., Liu, A., Zhang, Z., Li, X., Zou, Z., Zeng, W., Cheng, B., and Luo, S. (2005). Reactive oxygen species stimulates receptor activator of NF-${\kappa}B$ ligand expression in osteoblast. J. Biol. Chem. 280, 17497-17506 https://doi.org/10.1074/jbc.M409332200
  3. Bharti, A.C., Takada, Y., and Aggarwal, B.B. (2004). Curcumin(diferuloylmethane). inhibits receptor for activation of nuclear factor-${\kappa}B$ ligand induced NF-${\kappa}B$ activation in osteoclast precursors and suppress osteoclastogenesis. J. Immunol. 172, 5940-5947
  4. Brandstrom, H., Jonsson, K.B., Ohlsson, C., Vidal, O., Ljunghall, S., and Ljunggren, O. (1998). Regulation of osteoprotegerin mRNA levels by prostaglandin $E_2$ in human bone marrow stroma cells. Biochem. Biophys. Res. Commun. 247, 338-341 https://doi.org/10.1006/bbrc.1998.8783
  5. Cheng, A.L., Hsu, C.H., Lin, J.K., Hsu, M.M., Ho, Y.F., Shen, T.S., Ko, J.Y., Lin, J.T., Lin, B.R., Ming-Shiang, W., et al. (2001). Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res. 21, 2895-2900
  6. Darnay, B.G., Ni, J., Moore, P.A., and Aggarwal, B.B. (1999). Activation of nuclear factor-${\kappa}B$ by RANK requires tumor necrosis factor receptor-associated factor (TRAF). 6 and NF-${\kappa}B$ inducing kinase: identification of a novel TRAF6 interaction motif. J. Biol. Chem. 274, 7724-7731 https://doi.org/10.1074/jbc.274.12.7724
  7. Eghbali-Fatourechi, G., Khosla, S., Sanyal, A., Boyle, W.J., Lacey, D.L., and Riggs, B.L. (2003). Role of RANK ligand in mediating increased bone resorption in early postmenopausal women. J. Clin. Invest. 111, 1221-1230 https://doi.org/10.1172/JCI200317215
  8. Fraser, J.H., Helfrich, M.H., Wallace, H.M., and Ralston, S.H. (1996). Hydrogen peroxide, but not superoxide, stimulates bone resorption in mouse calvariae. Bone 19, 223-226 https://doi.org/10.1016/8756-3282(96)00177-9
  9. Gradisar, H., Keber, M.M., Pristovsek, P., and Jerala, R. (2007). MD-2 as the target of curcumin in the inhibition of response to LPS. J. Leukoc. Biol. 82, 968-974 https://doi.org/10.1189/jlb.1206727
  10. Kluth, D., Banning, A., Paur, I., Blomhoff, R., and Brigelius-Flohe, R. (2007). Modulation of pregnane X receptor and electrophile responsive element-mediated gene expression by dietary polyphenolic compounds. Free Radic. Biol. Med. 42, 315-325 https://doi.org/10.1016/j.freeradbiomed.2006.09.028
  11. Kong, Y.Y., Yoshida, H., Sarosi, I., Tan, H.L., Timms, E., Capparelli, C., Morony, S., Olivereira-dos-Santos, A.J., Van, G., Itie, A., et al. (1997). OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397, 315-323 https://doi.org/10.1038/16852
  12. Lean, J.M., Davies, J.T., Fuller, K., Jagger, C.J., Kirstein, B., Partington, G.A., Urry, Z.L., and Chamber, T.J. (2003). A crucial role for thiol antioxidants in estrogen-deficiency bone loss. J. Clin. Invest. 112, 915-923 https://doi.org/10.1172/JCI200318859
  13. Lee, S.K., and Lorenzo, J.A. (1999). Parathyroid hormone stimulates TRANCE and inhibits osteoprotegerin messenger ribonucleic acid expression in murine bone marrow cultures: correlation with osteoclast-like cell formation. Endocrinol. 140, 3552-3561 https://doi.org/10.1210/en.140.8.3552
  14. Lee, S.Y., Reichlin, A., Santana, A., Sokol, K.A., Nussenzweig, M.C., and Choi, Y. (1997). TRAF2 is essential for JNK but not NF-${\kappa}B$ activation and regulates lymphocytes proliferation and survival. Immunity 7, 703-713 https://doi.org/10.1016/S1074-7613(00)80390-8
  15. Lin, J.K. (2007). Molecular targets of curcumin. Adv. Exp. Med. Biol. 596, 227-243
  16. Mody, M., Parhami, F., Saraflan, T.A., and Demer, L.L. (2001). Oxidative stress modulates osteoblast differentiation of vascular and bone cells. Free Radic. Biol. Med. 31, 509-519 https://doi.org/10.1016/S0891-5849(01)00610-4
  17. Nishiumi, S., Yoshida, K., and Ashida, H. (2007). Curcumin suppresses the transformation of an aryl hydrocarbon receptor through its phosphorylation. Arch. Biochem. Biophys. 466, 267-273 https://doi.org/10.1016/j.abb.2007.08.007
  18. Ozaki, K., Kawata, Y., Amano, S., and Hanazawa, S. (2000). Stimulatory effect of curcumin on osteoclasst apoptosis. Biochem. Pharmacol. 59, 1577-1581 https://doi.org/10.1016/S0006-2952(00)00277-X
  19. Shin, H.H., Kim, S.J., Kang, S.Y., Lee, D.S., and Choi, H.S. (2006a). Soluble glucocorticoid induced tumor necrosis factor receptor stimulates osteoclastogenesis by down-regulation of osteoprotegerin in bone marrow stromal cells. Bone 39, 716-723 https://doi.org/10.1016/j.bone.2006.03.015
  20. Shin, H.H., Lee, J.E., Lee, E.A., Kwon, B.S., and Choi, H.S. (2006b). Enhanced osteoclastogenesis in 4-1BB-deficient mice caused by reduced interleukin-10. J. Bone Miner. Res. 21, 1907-1912 https://doi.org/10.1359/jbmr.060813
  21. 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. Endocrinol. Rev. 20, 345-357 https://doi.org/10.1210/er.20.3.345
  22. Suda, K., Udagawa, N., Sato, N., Takami, M., Itoh, K., Woo, J.-T., Takahashi, N., and Nagai, K. (2004). Suppression of osteoprotegerin expression by prostaglandin $E_2$ is crucially involved in lipopolysaccharide-induced osteoclast formation. J. Immunol. 172, 2504-2510 https://doi.org/10.4049/jimmunol.172.4.2504
  23. Tai, H., Miyaura, C., Pilbeam, C.C., Tamura, T., Ohsugi, Y., Koishihara, Y., Kubodera, N., Kawaguchi, H., Raisz, L.G., and Suda, T. (1997). Transcriptional induction of cyclooxygenase-2 in osteoblasts is involved in interleukin-6-induced osteoclast formation. Endocrinology 138, 2372-2379 https://doi.org/10.1210/en.138.6.2372
  24. Tropel, P., Noel, D., Platet, N., Legrand, P., Benabid, A.L., and Berger, F. (2004). Isolation and characterization of mesenchymal stem cells from adult mouse bone marrow. Exp. Cell Res. 295, 395-406 https://doi.org/10.1016/j.yexcr.2003.12.030
  25. Uchida, K. (2008). A lipid-derived endogenous inducer of COX-2: a bridge between inflammation and oxidative stress. Mol. Cell 25, 347-351
  26. Wong, B.R., Josien, R., Lee, S.Y., Vologodskaia, M., Steinman, R.M., and Choi, Y. (1998). The TRAF family of signal transducers mediates nuclear factor-${\kappa}B$ activation by the TRANCE receptor. J. Biol. Chem. 273, 28355-28359 https://doi.org/10.1074/jbc.273.43.28355
  27. 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