Sinulariolide Suppresses Inflammation of Fibroblast-Like Synoviocytes in Rheumatoid Arthritis and Mitigates Collagen-Induced Arthritis Symptoms in Mice

Sen-Wei Tsai,1,2 Yu-Chieh Cheng,3 Ya-Hsuan Chao,4 Deng-Ho Yang4– 7 1Department of Physical Medicine and Rehabilitation, Taichung Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taichung, 402, Taiwan; 2School of Medicine, Tzu Chi University, Hualien, 970, Taiwan; 3Department of Orthopaedics, Tungs’ Taichung Metro Harbor Hospital, Taichung, 433, Taiwan; 4The iEGG and Animal Biotechnology Center, National Chung Hsing University, Taichung, 402, Taiwan; 5Department of Internal Medicine, Taichung Armed-Forces General Hospital, Taichung, 411, Taiwan; 6Division of Rheumatology/Immunology/Allergy, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, 114, Taiwan; 7Department of Medical Laboratory Science and Biotechnology, Central Taiwan University of Science and Technology, Taichung, 406, TaiwanCorrespondence: Deng-Ho Yang, Department of Internal Medicine, Taichung Armed Forces General Hospital, No. 348, Sec. 2, Chung-Shan Road, Taiping Dist, Taichung, 41152, Taiwan, Tel +886-4-23934191, Fax +886-4-23934192, Email [email protected]: Rheumatoid arthritis (RA) is a systemic inflammatory disease characterized by active polyarthritis, which leads to functional loss and joint deformities. Natural compounds derived from marine organisms are considered valuable immune-modulating agents. This study aimed to assess the anti-inflammatory effect of sinulariolide, a soft coral-derived compound, on RA fibroblast-like synoviocytes and its therapeutic efficacy against collagen-induced arthritis (CIA).Methods: To determine the effects of sinulariolide on tumor necrosis factor-alpha (TNF-α)-induced inflammation, MH7A cells pre-treated with 10 ng/mL TNF-α for 24 h were treated with sinulariolide. The effect of sinulariolide on proinflammatory cytokine expressions at both the mRNA and protein levels in the MH7A cells was assessed using real-time-polymerase chain reaction and enzyme-linked immunosorbent assay (ELISA). Further, we analyzed the effect of sinulariolide on the activation of mitogen-activated protein kinase (MAPK) and nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathways using Western blotting and the TransAM NF-κB p65 kit. To comprehensively evaluate the potential application of sinulariolide in the treatment of inflammatory diseases, we used a well-established collagen-induced arthritis (CIA) mouse model. We examined the tissue sections of the ankle joints of the mice, assessed synovial hyperplasia, inflammatory cell infiltration, and cartilage damage, and used ELISA to analyze changes in cytokine expression in the hind paw tissues.Results: MH7A cells treated with sinulariolide showed a notable reduction in the expression of proinflammatory cytokines, which could be due to decreased activation of the MAPK and NF-kB pathways. Additionally, sinulariolide-treated mice showed significantly reduced joint swelling and lower clinical arthritis scores than those in the normal and control groups. Significant reductions in synovial hyperplasia, inflammatory cell infiltration, and cartilage damage were observed in the tissue sections of the ankle joints of the mice treated with sinulariolide. Furthermore, the expression of inflammatory cytokines in the hind paw tissue of the mice treated with sinulariolide was significantly decreased.Conclusion: Sinulariolide inhibited the progression of inflammation in MH7A cells. Sinulariolide treatment significantly reduced clinical arthritis symptoms and histological inflammatory responses in mice with CIA. Sinulariolide may serve as a potential therapeutic agent for RA.Keywords: fibroblast-like synoviocytes, soft coral, sinulariolide, inflammation, collagen-induced arthritis, rheumatoid arthritis