Obeticholic acid attenuates complete freund's adjuvant-induced arthritis in rats through FXR-mediated modulation of TGF-β/TAK1/MKK3/p38 MAPK signaling, inflammation, and oxidative stress.

Abstract

Rheumatoid arthritis is a chronic autoimmune inflammatory disorder characterized by synovial inflammation, oxidative stress, cartilage destruction, and progressive joint damage. Farnesoid X receptor activation has recently emerged as a potential regulator of immune and inflammatory responses. This study investigated the effect of obeticholic acid (OCA), a potent farnesoid X receptor agonist, in a complete Freund's adjuvant-induced arthritis model in rats, with emphasis on the TGF-β/TAK1/MKK3/p38 MAPK signaling pathway, inflammatory mediators, and oxidative stress.Arthritis was induced in male Wistar rats by subplantar injection of complete Freund's adjuvant on days 0 and 7. Rats were allocated into nine groups: normal control, OCA control, arthritic control, arthritic rats treated with OCA at 2.5 or 5 or 10 mg/kg, methotrexate-treated arthritic rats, F44-A13-treated arthritic rats, and arthritic rats co-treated with F44-A13 and OCA. Treatments were administered orally from day 8 for 14 consecutive days. Clinical arthritis severity, paw edema, pain behavior, body weight, immune organ weight, serological markers, inflammatory cytokines, oxidative stress markers, gene expression, and histopathological changes were evaluated.Obeticholic acid significantly ameliorated arthritic manifestations, as evidenced by reduced arthritis score, paw swelling, pain behavior, spleen and thymus weight, and improved body weight. It also decreased serum rheumatoid factor, C-reactive protein, and anti-cyclic citrullinated peptide levels. Obeticholic acid treatment was associated with restoration of FXR expression and downregulation of TGF-β, TGF-βR1, TAK1, MKK3, and p38 MAPK expression, accompanied by suppression of NF-κB, TNF-α, IFN-γ, IL-1β, and IL-6. In parallel, obeticholic acid enhanced antioxidant defenses by increasing Nrf2, superoxide dismutase, and catalase while reducing malondialdehyde levels. Histopathological assessment confirmed attenuation of synovial inflammation, cartilage damage, and proteoglycan loss. Co-administration of the FXR antagonist F44-A13 markedly blunted the protective effects of obeticholic acid.These findings indicate that OCA attenuates CFA-induced experimental arthritis and that these effects are associated with FXR-related changes in TGF-β/TAK1/MKK3/p38 MAPK gene expression, inflammatory mediators, and oxidative stress.

Key Findings

• Obeticholic acid significantly reduced arthritis severity, paw swelling, pain behavior, and immune organ weight while improving body weight in arthritic rats.
• Treatment decreased serum rheumatoid factor, C-reactive protein, and anti-cyclic citrullinated peptide levels, indicating reduced systemic inflammation.
• Obeticholic acid restored FXR expression and downregulated TGF-β/TAK1/MKK3/p38 MAPK signaling and pro-inflammatory cytokines including NF-κB, TNF-α, IFN-γ, IL-1β, and IL-6.
• The treatment enhanced antioxidant defenses by increasing Nrf2, superoxide dismutase, and catalase levels and reducing malondialdehyde, indicating reduced oxidative stress.
• Histopathological analysis confirmed attenuation of synovial inflammation and cartilage destruction.

Clinical Significance

Citation

Senna Mohamed Magdy, Shiha Nesma A, Zaki Hala Fet al.. Obeticholic acid attenuates complete freund's adjuvant-induced arthritis in rats through FXR-mediated modulation of TGF-β/TAK1/MKK3/p38 MAPK signaling, inflammation, and oxidative stress. Inflammopharmacology. 2026-Sep-18.