Flavonoid quercetin–methotrexate combination inhibits inflammatory mediators and matrix metalloproteinase expression, providing protection to joints in collagen-induced arthritis
- 52 Downloads
Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of synovial tissues in joints, leading to progressive destruction of cartilage and joints. The disease-modifying anti-rheumatic drugs currently in use have side-effects. Thus, there is an urgent need for safe anti-inflammatory therapies for RA. This study aimed to evaluate the therapeutic effect of the flavonoid quercetin on arthritis in mice immunized with type II collagen (CII). An arthritis model was established in C57/BL6 mice by intradermal administration of chicken CII mixed with Freund’s complete adjuvant. Quercetin (30 mg/kg orally) and methotrexate (0.75 mg intraperitoneally twice a week) were administered to investigate their protective effects against collagen-induced arthritis (CIA). Levels of tumour necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), IL-6, and the matrix metalloproteinases (MMP), 3, and 9 were detected to assess the anti-inflammatory effect of quercetin. The mRNA expression of MMP3, MMP9, CCL2, and TNF-α was also measured by quantitative real-time PCR. Quercetin significantly alleviated joint inflammation by reducing the levels of circulating cytokines and MMPs. There was a significant decrease in the expression of TNFα and MMP genes in the ankle joints of arthritic mice. A significant reduction in the levels of knee-joint inflammatory mediators were observed with combined quercetin and methotrexate treatment. Thus, quercetin has the potential to prevent joint inflammation and could be used as an adjunct therapy for RA patients who have an inadequate response to anti-rheumatic monotherapy.
KeywordsRheumatoid arthritis Flavonoids Inflammation Quercetin Methotrexate
This study was partially funded by a Grant from AITHM (Faculty Research Grant) and Arthritis Australia Grant 2015 to NH and NK. The Authors would like to thank Dr. Smrithi Krishna for her expert assistance in the gene expression studies.
NH and NK conceived and designed the study; NH, SMH, KH, SH, and AB performed the research; NH and SMH analysed data; NH, AB, and NK wrote the paper.
Compliance with ethical standards
Conflict of interest
The authors have declared no conflict of interest.
- Clark IM, Rowan AD, Cawston TE (2000) Matrix metalloproteinase inhibitors in the treatment of arthritis. Curr Opin Anti Inflamm Immunomodulat Invest Drugs 2:16–25Google Scholar
- Comalada M, Ballester I, Bailón E, Sierra S, Xaus J, Gálvez J, de Medina FS, Zarzuelo A (2006) Inhibition of pro-inflammatory markers in primary bone marrow-derived mouse macrophages by naturally occurring flavonoids: analysis of the structure–activity relationship. Biochem Pharmacol 72:1010–1021CrossRefPubMedGoogle Scholar
- Haringman JJ, Smeets TJ, Reinders-Blankert P, Tak PP (2006) Chemokine and chemokine receptor expression in paired peripheral blood mononuclear cells and synovial tissue of patients with rheumatoid arthritis, osteoarthritis, and reactive arthritis. Ann Rheum Dis 65(3):294–300CrossRefPubMedGoogle Scholar
- Lahiri M, Santosa A, Teoh LK, Clayton JA, Lim SY, Teng GG, Cheung PPM (2017) Use of complementary and alternative medicines is associated with delay to initiation of disease-modifying anti-rheumatic drug therapy in early inflammatory arthritis. Int J Rheum Dis 20(5):567–575CrossRefPubMedGoogle Scholar
- Mamani-Matsuda M, Kauss T, Al-Kharrat A, Rambert J, Fawaz F, Thiolat D, Moynet D, Coves S, Malvy D, Mossalayi MD (2006) Therapeutic and preventive properties of quercetin in experimental arthritis correlate with decreased macrophage inflammatory mediators. Biochem Pharmacol 72:1304–1310CrossRefPubMedGoogle Scholar
- Roeleveld DM, van Nieuwenhuijze AE, van den Berg WB, Koenders MI (2013) The Th17 pathway as a therapeutic target in rheumatoid arthritis and other autoimmune and inflammatory disorders. BioDrugs Clin Immunother Biopharm Gene Ther 27(5):439–452Google Scholar
- Roubille C, Richer V, Starnino T, McCourt C, McFarlane A, Fleming P et al (2015) The effects of tumour necrosis factor inhibitors, methotrexate, non-steroidal anti-inflammatory drugs and corticosteroids on cardiovascular events in rheumatoid arthritis, psoriasis and psoriatic arthritis: a systematic review and meta-analysis. Ann Rheum Dis 74:480–489CrossRefPubMedPubMedCentralGoogle Scholar
- Saragusti AC, Ortega MG, Cabrera JL, Estrin DA, Marti MA, Chiabrando GA (2010) Inhibitory effect of quercetin on matrix metalloproteinase 9 activity molecular mechanism and structure-activity relationship of the flavonoid-enzyme interaction. Eur J Pharmacol 644(1–3):138–145CrossRefPubMedGoogle Scholar
- Syggelos SA, Aletras AJ, Smirlaki I, Skandalis SS (2013) Extracellular matrix degradation and tissue remodeling in periprosthetic loosening and osteolysis: focus on matrix metalloproteinases, their endogenous tissue inhibitors, and the proteasome. Biomed Res Int 2013:230805CrossRefPubMedPubMedCentralGoogle Scholar
- Ye L, Wen Z, Li Y, Chen B, Yu T, Liu L, Zhang J, Ma Y, Xiao S, Ding L, Li L, Huang Z (2014) Interleukin-10 attenuation of collagen-induced arthritis is associated with suppression of interleukin-17 and retinoid-related orphan receptor γt production in macrophages and repression of classically activated macrophages. Arthritis Res Ther 16:R96CrossRefPubMedPubMedCentralGoogle Scholar