Anti-rheumatoid arthritis effects of chrysoeriol in a collagen-induced arthritis mouse model

Background: Rheumatoid arthritis (RA) is a chronic inflammatory disease. Fibroblast-like synoviocytes (FLS) play a pathogenic role in RA. Activation of STAT3 promotes proliferation and suppresses apoptosis of RA-FLS, resulting in synovial hyperplasia and joint damage. Chrysoeriol (CSR), a flavone found in diverse medicinal herbs, has been shown to have anti-inflammatory effects and inhibit STAT3 signaling.

Objective: This study aimed to determine whether CSR has anti-RA effects, and to investigate the involvement of STAT3 signaling in its effects.

Methods: A collagen-induced arthritis (CIA) mouse model was used to assess CSR’s in vivo anti-RA effects. IL-6/soluble IL-6 receptor (IL-6/sIL-6R)-stimulated RA-FLS were used to evaluate CSR’s in vitro effects.

Results: CSR attenuated paw swelling and bone erosion, suppressed synovial hyperplasia, down-regulated serum levels of TNF-α, IL-1β, IL-6 and IL-17, and improved body weight gain of CIA mice. CSR also down-regulated Th17 cell proportion, and up-regulated Treg cell proportion in splenocytes of CIA mice. In cell assays, CSR suppressed hyperproliferation of, and evoked apoptosis in, IL-6/sIL- 6R-stimulated RA-FLS. Mechanistic studies revealed that CSR inhibited activation/phosphorylation of STAT3 in synovial tissues of CIA mice and in IL-6/sIL-6R- stimulated RA-FLS. CRS also decreased STAT3 nuclear level and down-regulated protein levels of cleaved caspase-3, cleaved caspase-9, Bcl-2 and Mcl-1 in the cell model. Over-activation of STAT3 significantly diminished CSR’s anti-proliferative effects in IL-6/sIL-6R-stimulated RA- FLS.

Conclusions: We for the first time demonstrated that CSR ameliorates CIA in mice and suppresses hyperproliferation of RA-FLS. Inhibition of STAT3 signaling is involved in CSR’s anti-RA effects. This study provides a pharmacological basis for developing CSR into a novel anti-RA agent.