Flavonoid quercetin–methotrexate combination inhibits inflammatory mediators and matrix metalloproteinase expression, providing protection to joints in collagen-induced arthritis

Abstract

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.

Potential Advantages of Bioactive Compounds Extracted From Traditional Chinese Medicine to Inhibit Bone Destructions in Rheumatoid Arthritis

“…Quercetin and icariin are two other flavonoids with the effect of treating bone destruction in RA. Quercetin not only inhibited the expression of osteoclast-specific genes TRAP, CTSK, NFATc1 in vitro, and the plasma level of MMP-3, MMP-9 in CIA mice, but also up-regulated the mRNA and protein expression of osteoblast-specific genes Osx, Runx2, ALP and OCN (Guo C. et al, 2017;Haleagrahara et al, 2018;Kim H. R. et al, 2019). Icariin blocked osteoclast generation by inhibiting the expression of TRAF6 in the early stage of osteoclast formation and the activation of ERK1/2 and NF-kB.…”

Identification of Drug Targets and Potential Molecular Mechanisms of Wantong Jingu Tablet in Treatment of Rats with Collagen-Induced Arthritis based on 16S rDNA High-Throughput Sequencing and Metabolomic Analysis

“…On day 28, paw swelling and paw thickness were measured using a plethysmometer and an electronic vernier caliper, respectively. The severity of arthritis was evaluated using an arthritis index (AI) with a CIA semi-quantitative scoring system, as previously described by Nagaraja Haleagrahara et al [15].…”

Identification of drug targets and potential molecular mechanisms of Wantong Jingu Tablet in treatment of rats with collagen-induced arthritis based on 16S rDNA high-throughput sequencing and metabolomic analysis

“…On day 28, paw swelling and paw thickness were measured using a plethysmometer and an electronic vernier caliper, respectively. The severity of arthritis was evaluated using an arthritis index (AI) with a CIA semi-quantitative scoring system, as previously described by Nagaraja Haleagrahara et al [16].…”