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Inflammation

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Formononetin Antagonizes the Interleukin-1β-Induced Catabolic Effects Through Suppressing Inflammation in Primary Rat Chondrocytes

  • In-A Cho
  • Tae-Hyeon Kim
  • HyangI Lim
  • Jong-Hyun Park
  • Kyeong-Rok Kang
  • Sook-Young Lee
  • Chun Sung Kim
  • Do Kyung Kim
  • Heung-Joong Kim
  • Sun-Kyoung Yu
  • Su-Gwan Kim
  • Jae-Sung KimEmail author
ORIGINAL ARTICLE
  • 42 Downloads

Abstract

In the present study, we demonstrated the anti-catabolic effects of formononetin, a phytoestrogen derived from herbal plants, against interleukin-1β (IL-1β)-induced severe catabolic effects in primary rat chondrocytes and articular cartilage. Formononetin did not affect the viability of primary rat chondrocytes in both short- (24 h) and long-term (21 days) treatment periods. Furthermore, formononetin effectively antagonized the IL-1β-induced catabolic effects including the decrease in proteoglycan content, suppression of pericellular matrix formation, and loss of proteoglycan through the decreased expression of cartilage-degrading enzymes like matrix metalloproteinase (MMP)-13, MMP-1, and MMP-3 in primary rat chondrocytes. Moreover, catabolic oxidative stress mediators like nitric oxide, inducible nitric oxide synthase, cyclooxygenase-2, and prostaglandin E2 were significantly downregulated by formononetin in primary rat chondrocytes treated with IL-1β. Sequentially, the upregulation of pro-inflammatory cytokines (like IL-1α, IL-1β, IL-6, and tumor necrosis factor α), chemokines (like fractalkine, monocyte chemoattractant protein-1, and macrophage inflammatory protein-3α), and vascular endothelial growth factor were significantly downregulated by formononetin in primary rat chondrocytes treated with IL-1β. These data suggest that formononetin may suppress IL-1β-induced severe catabolic effects and osteoarthritic condition. Furthermore, formononetin may be a promising candidate for the treatment and prevention of osteoarthritis.

KEY WORDS

osteoarthritis articular cartilage chondrocyte inflammation formononetin 

Notes

Acknowledgments

This study was supported by research fund from Chosun University, 2017.

Author’s Contributions

I.A.C, T.H.K., K.R.K, H.L., J.H.P., S.Y.L., and J.S.K. contributed to the experimental design and collected the data. C.S.K., D.K.K., H.K.K., S.K.Y., S.G.K., and J.S.K. contributed to the data analysis and interpretation. I.A.C., K.R.K., and J.S.K. did the writing article.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflicts of interest.

References

  1. 1.
    Goldring, M.B., and S.R. Goldring. 2007. Osteoarthritis. Journal of Cellular Physiology 213: 626–634.CrossRefGoogle Scholar
  2. 2.
    Barr, A.J., T.M. Campbell, D. Hopkinson, S.R. Kingsbury, M.A. Bowes, and P.G. Conaghan. 2015. A systematic review of the relationship between subchondral bone features, pain and structural pathology in peripheral joint osteoarthritis. Arthritis Research & Therapy 17: 228.CrossRefGoogle Scholar
  3. 3.
    Xie, F., B. Kovic, X. Jin, X. He, M. Wang, and C. Silvestre. 2016. Economic and humanistic burden of osteoarthritis: A systematic review of large sample studies. Pharmacoeconomics 34: 1087–1100.CrossRefGoogle Scholar
  4. 4.
    Chen, D., J. Shen, W. Zhao, T. Wang, L. Han, J.L. Hamilton, and H.J. Im. 2017. Osteoarthritis: Toward a comprehensive understanding of pathological mechanism. Bone Research 5: 16044.CrossRefGoogle Scholar
  5. 5.
    Zhang, W., H. Ouyang, C.R. Dass, and J. Xu. 2016. Current research on pharmacologic and regenerative therapies for osteoarthritis. Bone Research 4: 15040.CrossRefGoogle Scholar
  6. 6.
    Luria, A., and C.R. Chu. 2014. Articular cartilage changes in maturing athletes: New targets for joint rejuvenation. Sports Health 6: 18–30.CrossRefGoogle Scholar
  7. 7.
    Kim, H., D. Kang, Y. Cho, and J.H. Kim. 2015. Epigenetic regulation of chondrocyte catabolism and anabolism in osteoarthritis. Molecules and Cells 38: 677–684.CrossRefGoogle Scholar
  8. 8.
    Lee, A.S., M.B. Ellman, D. Yan, J.S. Kroin, B.J. Cole, A.J. van Wijnen, and H.J. Im. 2013. A current review of molecular mechanisms regarding osteoarthritis and pain. Gene 527: 440–447.CrossRefGoogle Scholar
  9. 9.
    Akkiraju, H., and A. Nohe. 2015. Role of chondrocytes in cartilage formation, progression of osteoarthritis and cartilage regeneration. Journal of Developmental Biology 3: 177–192.CrossRefGoogle Scholar
  10. 10.
    Nie, T., S. Zhao, L. Mao, Y. Yang, W. Sun, X. Lin, S. Liu, K. Li, Y. Sun, P. Li, Z. Zhou, S. Lin, X. Hui, A. Xu, C.W. Ma, Y. Xu, C. Wang, P.R. Dunbar, and D. Wu. 2018. The natural compound, formononetin, extracted from Astragalus membranaceus increases adipocyte thermogenesis by modulating PPARgamma activity. British Journal of Pharmacology 175: 1439–1450.CrossRefGoogle Scholar
  11. 11.
    Mu, H., Y.H. Bai, S.T. Wang, Z.M. Zhu, and Y.W. Zhang. 2009. Research on antioxidant effects and estrogenic effect of formononetin from Trifolium pratense (red clover). Phytomedicine 16: 314–319.CrossRefGoogle Scholar
  12. 12.
    Ma, Z., W. Ji, Q. Fu, and S. Ma. 2013. Formononetin inhibited the inflammation of LPS-induced acute lung injury in mice associated with induction of PPAR gamma expression. Inflammation 36: 1560–1566.CrossRefGoogle Scholar
  13. 13.
    Wu, J., X. Ke, N. Ma, W. Wang, W. Fu, H. Zhang, M. Zhao, X. Gao, X. Hao, and Z. Zhang. 2016. Formononetin, an active compound of Astragalus membranaceus (Fisch) Bunge, inhibits hypoxia-induced retinal neovascularization via the HIF-1alpha/VEGF signaling pathway. Drug Design, Development and Therapy 10: 3071–3081.CrossRefGoogle Scholar
  14. 14.
    Xia, B., Chen Di, J. Zhang, S. Hu, H. Jin, and P. Tong. 2014. Osteoarthritis pathogenesis: A review of molecular mechanisms. Calcified Tissue International 95: 495–505.CrossRefGoogle Scholar
  15. 15.
    Cameron, M., and S. Chrubasik. 2014. Oral herbal therapies for treating osteoarthritis. Cochrane Database of Systematic Reviews CD002947.Google Scholar
  16. 16.
    Greene, M.A., and R.F. Loeser. 2015. Aging-related inflammation in osteoarthritis. Osteoarthritis and Cartilage 23: 1966–1971.CrossRefGoogle Scholar
  17. 17.
    Rezuș, E., A. Cardoneanu, A. Burlui, A. Luca, C. Codreanu, B.I. Tamba, G.D. Stanciu, N. Dima, C. Bădescu, and C. Rezuș. 2019. The link between inflammaging and degenerative joint diseases. International Journal of Molecular Sciences: 20.Google Scholar
  18. 18.
    Nees, T.A., N. Rosshirt, T. Reiner, M. Schiltenwolf, and B. Moradi. 2018. Inflammation and osteoarthritis-related pain. Der Schmerz.Google Scholar
  19. 19.
    Mathiessen, A., and P.G. Conaghan. 2017. Synovitis in osteoarthritis: Current understanding with therapeutic implications. Arthritis Research & Therapy 19: 18.CrossRefGoogle Scholar
  20. 20.
    Abramson, S.B. 2008. Nitric oxide in inflammation and pain associated with osteoarthritis. Arthritis Research & Therapy 10: S2.CrossRefGoogle Scholar
  21. 21.
    Notoya, K., D.V. Jovanovic, P. Reboul, J. Martel-Pelletier, F. Mineau, and J.P. Pelletier. 2000. The induction of cell death in human osteoarthritis chondrocytes by nitric oxide is related to the production of prostaglandin E2 via the induction of cyclooxygenase-2. Journal of Immunology 165: 3402–3410.CrossRefGoogle Scholar
  22. 22.
    Park, J.Y., M.H. Pillinger, and S.B. Abramson. 2006. Prostaglandin E2 synthesis and secretion: The role of PGE2 synthases. Clinical Immunology 119: 229–240.CrossRefGoogle Scholar
  23. 23.
    Schuerwegh, A.J., E.J. Dombrecht, W.J. Stevens, J.F. Van Offel, C.H. Bridts, and L.S. De Clerck. 2003. Influence of pro-inflammatory (IL-1 alpha, IL-6, TNF-alpha, IFN-gamma) and anti-inflammatory (IL-4) cytokines on chondrocyte function. Osteoarthritis and Cartilage 11: 681–687.CrossRefGoogle Scholar
  24. 24.
    Caglic, D., U. Repnik, C. Jedeszko, G. Kosec, C. Miniejew, M. Kindermann, O. Vasiljeva, et al. 2013. The proinflammatory cytokines interleukin-1alpha and tumor necrosis factor alpha promote the expression and secretion of proteolytically active cathepsin S from human chondrocytes. Biological Chemistry 394: 307–316.CrossRefGoogle Scholar
  25. 25.
    Richardson, D.W., and G.R. Dodge. 2000. Effects of interleukin-1beta and tumor necrosis factor-alpha on expression of matrix-related genes by cultured equine articular chondrocytes. American Journal of Veterinary Research 61: 624–630.CrossRefGoogle Scholar
  26. 26.
    Heraud, F., A. Heraud, and M.F. Harmand. 2000. Apoptosis in normal and osteoarthritic human articular cartilage. Annals of the Rheumatic Diseases 59: 959–965.CrossRefGoogle Scholar
  27. 27.
    Mohtai, M., M.K. Gupta, B. Donlon, B. Ellison, J. Cooke, G. Gibbons, D.J. Schurman, and R.L. Smith. 1996. Expression of interleukin-6 in osteoarthritic chondrocytes and effects of fluid-induced shear on this expression in normal human chondrocytes in vitro. Journal of Orthopaedic Research 14: 67–73.CrossRefGoogle Scholar
  28. 28.
    Zhou, R., X. Wu, Z. Wang, J. Ge, and F. Chen. 2015. Interleukin-6 enhances acid-induced apoptosis via upregulating acid-sensing ion channel 1a expression and function in rat articular chondrocytes. International Immunopharmacology 29: 748–760.CrossRefGoogle Scholar
  29. 29.
    Sandell, L.J., X. Xing, C. Franz, S. Davies, L.W. Chang, and D. Patra. 2008. Exuberant expression of chemokine genes by adult human articular chondrocytes in response to IL-1beta. Osteoarthritis and Cartilage 16: 1560–1571.CrossRefGoogle Scholar
  30. 30.
    Zou, Y., Y. Li, L. Lu, Y. Lin, W. Liang, Z. Su, X. Wang, H. Yang, J. Wang, C. Yu, L. Huo, and Y. Ye. 2013. Correlation of fractalkine concentrations in serum and synovial fluid with the radiographic severity of knee osteoarthritis. Annals of Clinical Biochemistry 50: 571–575.CrossRefGoogle Scholar
  31. 31.
    Huo, L.W., Y.L. Ye, G.W. Wang, and Y.G. Ye. 2015. Fractalkine (CX3CL1): A biomarker reflecting symptomatic severity in patients with knee osteoarthritis. Journal of Investigative Medicine 63: 626–631.CrossRefGoogle Scholar
  32. 32.
    Klosowska, K., M.V. Volin, N. Huynh, K.K. Chong, M.M. Halloran, and J.M. Woods. 2009. Fractalkine functions as a chemoattractant for osteoarthritis synovial fibroblasts and stimulates phosphorylation of mitogen-activated protein kinases and Akt. Clinical & Experimental Immunology 156: 312–319.CrossRefGoogle Scholar
  33. 33.
    Wojdasiewicz, P., L.A. Poniatowski, A. Kotela, J. Deszczynski, I. Kotela, and D. Szukiewicz. 2014. The chemokine CX3CL1 (fractalkine) and its receptor CX3CR1: Occurrence and potential role in osteoarthritis. Archivum Immunologiae et Therapiae Experimentalis 62: 395–403.CrossRefGoogle Scholar
  34. 34.
    Xu, Y.K., Y. Ke, B. Wang, and J.H. Lin. 2015. The role of MCP-1-CCR2 ligand-receptor axis in chondrocyte degradation and disease progress in knee osteoarthritis. Biological Research 48: 64.CrossRefGoogle Scholar
  35. 35.
    Alaaeddine, N., J. Antoniou, M. Moussa, G. Hilal, G. Kreichaty, I. Ghanem, W. Abouchedid, E. Saghbini, and J.A. Di Battista. 2015. The chemokine CCL20 induces proinflammatory and matrix degradative responses in cartilage. Inflammation Research 64: 721–731.CrossRefGoogle Scholar
  36. 36.
    Lingaraj, K., C.K. Poh, and W. Wang. 2010. Vascular endothelial growth factor (VEGF) is expressed during articular cartilage growth and re-expressed in osteoarthritis. Annals of the Academy of Medicine, Singapore 39: 399–403.Google Scholar
  37. 37.
    Zhang, X., R. Crawford, and Y. Xiao. 2016. Inhibition of vascular endothelial growth factor with shRNA in chondrocytes ameliorates osteoarthritis. Journal of Molecular Medicine 94: 787–798.CrossRefGoogle Scholar
  38. 38.
    Barranco, C. 2014. Osteoarthritis: Animal data show VEGF blocker inhibits post-traumatic OA. Nature Reviews Rheumatology 10: 638.CrossRefGoogle Scholar
  39. 39.
    Miller, R.E., R.J. Miller, and A.M. Malfait. 2014. Osteoarthritis joint pain: The cytokine connection. Cytokine 70: 185–193.CrossRefGoogle Scholar
  40. 40.
    Hamilton, J.L., M. Nagao, B.R. Levine, D. Chen, B.R. Olsen, and H.J. Im. 2016. Targeting VEGF and its receptors for the treatment of osteoarthritis and associated pain. Journal of Bone and Mineral Research 31: 911–924.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • In-A Cho
    • 1
  • Tae-Hyeon Kim
    • 1
  • HyangI Lim
    • 1
  • Jong-Hyun Park
    • 1
  • Kyeong-Rok Kang
    • 1
  • Sook-Young Lee
    • 1
    • 2
  • Chun Sung Kim
    • 1
    • 2
  • Do Kyung Kim
    • 1
  • Heung-Joong Kim
    • 1
  • Sun-Kyoung Yu
    • 1
  • Su-Gwan Kim
    • 1
  • Jae-Sung Kim
    • 1
    Email author
  1. 1.Oral Biology Research Institute, School of DentistryChosun UniversityGwangjuRepublic of Korea
  2. 2.Marine Bio Research CenterChosun UniversityWando-gunRepublic of Korea

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