Fraxinellone Attenuates Rheumatoid Inflammation in Mice.

Seung Jung,Seung-Ki Kwok,Se Jang,Jin-Sil Park,Seung Baek,Mi-La Cho,Sung-Hwan Park,Jaeseon Lee,Juhyun Lee,Seung-Min Hong

doi:10.3390/ijms19030829

Abstract

This study aimed to evaluate the therapeutic effect of fraxinellone on inflammatory arthritis and identify the underlying mechanisms. Fraxinellone (7.5 mg/kg) or a vehicle control was injected into mice with collagen-induced arthritis (CIA). The severity of arthritis was evaluated clinically and histologically. The differentiation of CD4+ T cells and CD19+ B cells was investigated in the presence of fraxinellone. Osteoclastogenesis after fraxinellone treatment was evaluated by staining with tartrate-resistant acid phosphatase (TRAP) and by measuring the mRNA levels of osteoclastogenesis-related genes. Fraxinellone attenuated the clinical and histologic features of inflammatory arthritis in CIA mice. Fraxinellone suppressed the production of interleukin-17 and the expression of RAR-related orphan receptor γ t and phospho-signal transducer and activator of transcription 3 in CD4+ T cells. CD19+ B cells showed lower expression of activation-induced cytidine deaminase and B lymphocyte-induced maturation protein-1 after treatment with fraxinellone. The formation of TRAP-positive cells and the expression of osteoclastogenesis-related markers were reduced in the presence of fraxinellone. Inhibition of interleukin-17 and osteoclastogenesis was also observed in experiments using human peripheral mononuclear cells. Fraxinellone alleviated synovial inflammation and osteoclastogenesis in mice. The therapeutic effect of fraxinellone was associated with the inhibition of cellular differentiation and activation. The data suggests that fraxinellone could be a novel treatment for inflammatory arthritis, including rheumatoid arthritis.

Highlights

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by inflammatory polyarthritis that lead to joint destruction and functional disability
This study aimed to evaluate the therapeutic effect of fraxinellone in mice with inflammatory arthritis and identify the underlying mechanisms that contribute to alleviating inflammatory arthritis
Either fraxinellone (7.5 mg/kg) or a vehicle control was administered intraperitoneally into collagen-induced arthritis (CIA) mice in order to evaluate the therapeutic effects of fraxinellone on inflammatory arthritis

Summary

Introduction

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by inflammatory polyarthritis that lead to joint destruction and functional disability. The pathogenesis of RA still remains to be determined, but the interplay between various immune cells would be critical in the development and progression of RA [1]. The pathologic roles of T cells have been extensively studied, and the inflammatory subset of T cells producing interleukin (IL)-17 (Th17 cells) is considered to play a key role in the pathogenesis of inflammatory arthritis [2]. IL-17 stimulates RA synoviocytes to produce IL-6, which promotes the production of proinflammatory mediators, such as IL-1β, tumor necrosis factor-alpha (TNF-α), and matrix metalloproteinase, and accelerates synovial inflammation and bone destruction. IL-17 induces the expression of receptor activator of nuclear factor-κB (RANK) ligand (RANKL), and accelerates erosion of bone. B cells producing specific autoantibodies contribute to the pathogenesis of RA. Treatment of RA aims to suppress the inflammatory response provoked by these immune cells, and reduce the synovitis and osteoclastogenesis [5]

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