Skip to main content

Advertisement

SpringerLink
Log in

Kaempferol Inhibits IL-1β-Stimulated, RANKL-mediated Osteoclastogenesis via Downregulation of MAPKs, c-Fos, and NFATc1

  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Kaempferol is one of the most common flavonoid that is present in a variety of vegetables and fruits and has effects on bone metabolism. The present study was performed to define the effects of kaempferol on interleukin (IL)-1β-stimulated receptor activator of NF-κB ligand (RANKL)-mediated osteoclast differentiation. Bone marrow cells were harvested from 6-week-old male imprinting control region mice, and the differentiation of osteoclasts from these cells was evaluated by tartrate-resistant acid phosphatase staining and resorption pit formation assay. Phosphorylated extracellular signal-regulated kinase (p-ERK), phosphorylated p38, phosphorylated c-Jun amino-terminal kinase, NF-κB (p65), IκBα, c-Fos, and nuclear factor of activated T cells c1 (NFATc1) expressions were examined by Western blotting and quantitative RT-PCR. Kaempferol inhibits IL-1β-stimulated, RANKL-mediated osteoclast differentiation and also inhibits IL-1β-stimulated, RANKL-mediated phosphorylation of ERK 1/2, p38 and JNK MAP kinases, and expressions of c-Fos and NFATc1. These results indicate that kaempferol has an inhibitory role in the bone loss by preventing osteoclast formation and suggest that it might be a novel therapeutic agent for the treatment of inflammatory arthritis by managing bone destruction.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Suda, T., N. Takahashi, N. Udagawa, E. Jimi, M.T. Gillespie, and T.J. Martin. 1999. Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocrine Reviews 20: 345–357.

    Article  CAS  PubMed  Google Scholar 

  2. Abu-Amer, Y., F.P. Ross, J. Edwards, and S.L. Teitelbaum. 1997. Lipopolysaccharide-stimulated osteoclastogenesis is mediated by tumor necrosis factor via its P55 receptor. The Journal of Clinical Investigation 100: 1557–1565.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Hofbauer, L.C., S. Khosla, C.R. Dunstan, D.L. Lacey, W.J. Boyle, and B.L. Riggs. 2000. The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption. Journal of Bone and Mineral Research 15: 2–12.

    Article  CAS  PubMed  Google Scholar 

  4. Lee, Z.H., and H.H. Kim. 2003. Signal transduction by receptor activator of nuclear factor kappa B in osteoclasts. Biochemical and Biophysical Research Communications 305: 211–214.

    Article  CAS  PubMed  Google Scholar 

  5. Teitelbaum, S.L., and F.P. Ross. 2003. Genetic regulation of osteoclast development and function. Nature Reviews. Genetics 4: 638–649.

    Article  CAS  PubMed  Google Scholar 

  6. Matsuo, K., D.L. Galson, C. Zhao, L. Peng, C. Laplace, K.Z. Wang, et al. 2004. Nuclear factor of activated T-cells (NFAT) rescues osteoclastogenesis in precursors lacking c-Fos. The Journal of Biological Chemistry 279: 26475–26480.

    Article  CAS  PubMed  Google Scholar 

  7. Takayanagi, H., S. Kim, T. Koga, H. Nishina, M. Isshiki, H. Yoshida, et al. 2002. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Developmental Cell 3: 889–901.

    Article  CAS  PubMed  Google Scholar 

  8. Bosetti, C., M. Rossi, J.K. McLaughlin, E. Negri, R. Talamini, P. Lagiou, et al. 2007. Flavonoids and the risk of renal cell carcinoma. Cancer Epidemiology, Biomarkers and Prevention 16: 98–01.

    Article  CAS  PubMed  Google Scholar 

  9. Guo, Q., L. Zhao, Q. You, Y. Yang, H. Gu, G. Song, et al. 2007. Anti-hepatitis B virus activity of wogonin in vitro and in vivo. Antiviral Research 74: 16–24.

    Article  CAS  PubMed  Google Scholar 

  10. Cárdenas, M., M. Marder, V.C. Blank, and L.P. Roquin. 2006. Antitumor activity of some natural flavonoids and synthetic derivatives on various human and murine cancer cell lines. Bioorganic and Medicinal Chemistry 14: 2966–2971.

    Article  PubMed  Google Scholar 

  11. Burda, S., and W. Oleszek. 2001. Antioxidant and antiradical activities of flavonoids. Journal of Agricultural and Food Chemistry 49: 2774–2779.

    Article  CAS  PubMed  Google Scholar 

  12. González-Gallego, J., S. Sánchez-Campos, and M.J. Tuñón. 2007. Anti-inflammatory properties of dietary flavonoids. Nutrición Hospitalaria 22: 287–293.

    PubMed  Google Scholar 

  13. Olszewska, M. 2008. Separation of quercetin, sexangularetin, kaempferol and isorhamnetin for simultaneous HPLC determination of flavonoid aglycones in inflorescences, leaves and fruits of three Sorbus species. Journal of Pharmaceutical and Biomedical Analysis 48: 629–635.

    Article  CAS  PubMed  Google Scholar 

  14. Kim, S.K., H.J. Kim, S.E. Choi, K.H. Park, H.K. Choi, and M.W. Lee. 2008. Anti-oxidative and inhibitory activities on nitric oxide (NO) and prostaglandin E2 (COX-2) production of flavonoids from seeds of Prunus tomentosa Thunberg. Archives of Pharmacal Research 31: 424–428.

    Article  CAS  PubMed  Google Scholar 

  15. Kim, H.K., H.R. Park, J.S. Lee, T.S. Chung, H.Y. Chung, and J. Chung. 2007. Down-regulation of iNOS and TNF-alpha expression by kaempferol via NF-kappaB inactivation in aged rat gingival tissues. Biogerontology 8: 399–408.

    Article  CAS  PubMed  Google Scholar 

  16. Yoon, H.Y., E.G. Lee, H. Lee, I.J. Cho, Y.J. Choi, M.S. Sung, et al. 2013. Kaempferol inhibits IL-1β-induced proliferation of rheumatoid arthritis synovial fibroblasts and the production of COX-2, PGE2 and MMPs. International Journal of Molecular Medicine 32: 971–977.

    CAS  PubMed  Google Scholar 

  17. Pang, J.L., D.A. Ricupero, S. Huang, N. Fatma, D.P. Singh, J.R. Romero, et al. 2006. Differential activity of kaempferol and quercetin in attenuating tumor necrosis factor receptor family signaling in bone cells. Biochemical Pharmacology 71: 818–826.

    Article  CAS  PubMed  Google Scholar 

  18. Yamaguchi, M., R. Hamamoto, S. Uchiyama, and K. Ishiyama. 2007. Effects of flavonoid on calcium content in femoral tissue culture and parathyroid hormone-stimulated osteoclastogenesis in bone marrow culture in vitro. Molecular and Cellular Biochemistry 303: 83–88.

    Article  CAS  PubMed  Google Scholar 

  19. Wattel, A., S. Kamel, R. Mentaverri, F. Lorget, C. Prouillet, J.P. Petit, et al. 2003. Potent inhibitory effect of naturally occurring flavonoids quercetin and kaempferol on in vitro osteoclastic bone resorption. Biochemical Pharmacology 65: 35–42.

    Article  CAS  PubMed  Google Scholar 

  20. Nakagawa, T., M. Takahashi, T. Ozaki, Ki.K. Watanabe, S. Todo, H. Mizuguchi, et al. 2002. Autoinhibitory regulation of p73 by Delta Np73 to modulate cell survival and death through a p73-specific target element within the Delta Np73 promoter. Molecular and Cellular Biology 22: 2575–2585.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Noh, E.M., J.S. Kim, H. Hur, B.H. Park, E.K. Song, M.K. Han, et al. 2009. Cordycepin inhibits IL-1beta-induced MMP-1 and MMP-3 expression in rheumatoid arthritis synovial fibroblasts. Rheumatology (Oxford) 48: 45–48.

    Article  CAS  Google Scholar 

  22. Cortes, J.R., M. Perez-G, M.D. Rivas, and J. Zamorano. 2007. Kaempferol inhibits IL-4-induced STAT6 activation by specifically targeting JAK3. The Journal of Immunology 179: 3881–3887.

    Article  CAS  PubMed  Google Scholar 

  23. García-Mediavilla, V., I. Crespo, P.S. Collado, A. Esteller, S. Sánchez-Campos, M.J. Tuñón, et al. 2007. The anti-inflammatory flavones quercetin and kaempferol cause inhibition of inducible nitric oxide synthase, cyclooxygenase-2 and reactive C-protein, and down-regulation of the nuclear factor kappaB pathway in Chang Liver cells. European Journal of Pharmacology 557: 221–229.

    Article  PubMed  Google Scholar 

  24. Gates, M.A., S.S. Tworoger, J.L. Hecht, I. De Vivo, B. Rosner, and S.E. Hankinson. 2007. A prospective study of dietary flavonoid intake and incidence of epithelial ovarian cancer. International Journal of Cancer 121: 2225–2232.

    Article  CAS  Google Scholar 

  25. Nöthlings, U., S.P. Murphy, L.R. Wilkens, B.E. Henderson, and L.N. Kolonel. 2007. Flavonols and pancreatic cancer risk: the multiethnic cohort study. American Journal of Epidemiology 166: 924–931.

    Article  PubMed  Google Scholar 

  26. Garcia-Closas, R., C.A. Gonzalez, A. Aqudo, and E. Riboli. 1999. Intake of specific carotenoids and flavonoids and the risk of gastric cancer in Spain. Cancer Causes and Control 10: 71–75.

    Article  CAS  PubMed  Google Scholar 

  27. Cawston, T.E. 1995. Proteinases and connective tissue breakdown. In Mechanisms and Models in Rheumatoid Arthritis, ed. B. Henderson, J.C.W. Edwards, and E.R. Pettipher, 333–359. London: Academic Press.

    Chapter  Google Scholar 

  28. Han, M.K., J.S. Kim, B.H. Park, J.R. Kim, B.Y. Hwang, H.Y. Lee, et al. 2003. NF-kappaB-dependent lymphocyte hyperadhesiveness to synovial fibroblasts by hypoxia and reoxygenation: potential role in rheumatoid arthritis. Journal of Leukocyte Biology 73: 525–529.

    Article  CAS  PubMed  Google Scholar 

  29. Gitter, B.D., J.M. Labus, S.L. Lees, and M.E. Scheetz. 1989. Characteristics of human synovial fibroblast activation by IL-1 beta and TNF alpha. Immunology 66: 196–200.

    CAS  PubMed Central  PubMed  Google Scholar 

  30. Takayanagi, H. 2005. Mechanistic insight into osteoclast differentiation in osteoimmunology. Journal of Molecular Medicine 83: 170–179.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This paper was supported by the research funds of Chonbuk National University in 2012.

Conflict of Interest

The authors state that there was no potential conflict of interest relevant to this article.

Author information

Authors and Affiliations

  1. Department of Internal Medicine, Chonbuk National University Medical School and Research Institute of Clinical Medicine of Chonbuk National University Hospital-Chonbuk National University, 561-180, Jeonbuk, Jeonju, Republic of Korea

    Won-Seok Lee, Eun-Gyeong Lee, Myung-Soon Sung & Wan-Hee Yoo

  2. Division of Rheumatology, Department of Internal Medicine, Chonbuk National University Medical School and Research Institute of Clinical Medicine of Chonbuk National University Hospital-Chonbuk National University, San 2-20 Geumam-dong, Deokjin-gu, Jeonju, Jeonbuk, 561-180, South Korea

    Won-Seok Lee, Eun-Gyeong Lee, Myung-Soon Sung & Wan-Hee Yoo

Authors
  1. Won-Seok Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eun-Gyeong Lee
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Myung-Soon Sung
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wan-Hee Yoo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wan-Hee Yoo.

Additional information

Won-Seok Lee and Eun-Gyeong Lee equally contributed to this paper

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lee, WS., Lee, EG., Sung, MS. et al. Kaempferol Inhibits IL-1β-Stimulated, RANKL-mediated Osteoclastogenesis via Downregulation of MAPKs, c-Fos, and NFATc1. Inflammation 37, 1221–1230 (2014). https://doi.org/10.1007/s10753-014-9849-6

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-014-9849-6

KEY WORDS

Search

Navigation