Formononetin Antagonizes the Interleukin-1β-Induced Catabolic Effects Through Suppressing Inflammation in Primary Rat Chondrocytes
- 42 Downloads
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 WORDSosteoarthritis articular cartilage chondrocyte inflammation formononetin
This study was supported by research fund from Chosun University, 2017.
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.
- 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
- 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
- 15.Cameron, M., and S. Chrubasik. 2014. Oral herbal therapies for treating osteoarthritis. Cochrane Database of Systematic Reviews CD002947.Google Scholar
- 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.Nees, T.A., N. Rosshirt, T. Reiner, M. Schiltenwolf, and B. Moradi. 2018. Inflammation and osteoarthritis-related pain. Der Schmerz.Google Scholar
- 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
- 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.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
- 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
- 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
- 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