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Ethnopharmacological Relevance: Eucommia ulmoides Oliv., a valuable Chinese herb, has shown a variety of health benefits. Despite the widespread clinical use of this herb to treat rheumatoid arthritis (RA) in Traditional Chinese Medicine (TCM), very few studies have described its anti-pathological effects or mechanism in RA. The present study investigated the mechanism of Eucommia ulmoides Oliv. in an experimental collagen-induced arthritis (CIA) rat model., Materials and Methods: The effects of four different Eucommia ulmoides Oliv. extracts on the proliferation of rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS) were screened in an MTT assay, and apoptotic effects were detected by flow cytometry. Among the extracts, the 70% ethanol extract (EU70) presented the best inhibition and was further investigated for its curative effect in CIA rats. Foot swelling was detected, and the arthritis index (AI) was scored. Pathological improvement was assessed by haematoxylin and eosin (H&E) staining of joint tissues. The mechanistic effects of EU70 were investigated as follows: anti-inflammatory effects in Th17-positive cells by flow cytometry; serum levels of inflammatory cytokines by ELISA; TNFα and IL-1β expression by immunohistochemistry (IHC); and anti-osteoclastogenesis by QPCR detection of RANKL and OPG mRNA., Results: Compared with vehicle treatment in CIA model rats, EU70 significantly ameliorated foot swelling, decreased AI in vivo and reduced inflammatory cell infiltration and synoviocyte proliferation. EU70 decreased the number of Th17-positive cells in the spleen and the serum levels of cytokines, including IL-17, IL-1β and TNFα, and upregulated the serum levels of IL-10; these results indicated the anti-inflammatory effect of EU70. Moreover, EU70 effectively suppressed TNFα and IL-1β expression in the joint tissues and resulted in the downregulation of RANKL mRNA and the upregulation of OPG mRNA. These results revealed the possible preventive role of EU70 against bone destruction., Conclusion: For the first time, these mechanisms and pathological improvements support the clinical use of Eucommia ulmoides Oliv. in treating RA. The findings indicated that the 70% ethanol extract of Eucommia ulmoides Oliv. could relieve RA symptoms by (1) suppressing the proliferation of synoviocytes, (2) reducing the number of Th17-positive cells and downregulating serum IL-17 expression, (3) increasing the anti-inflammatory effects of IL-10, (4) inhibiting the serum and tissue levels of key pro-inflammatory cytokines, TNFα and IL-1β, and (5) reducing the degradation of cartilage and bone., (Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.)