Combination of High-Molecular-Weight Hyaluronic Acid and Cytokine Inhibitor Potently Inhibits Expression of Joint-Damage-Related Genes Induced By Synovial Fluid of RA Patients

Misato Hashizume,Masahiko Mihara

doi:10.4172/2167-7921.1000117

Abstract

Background: Blockade of inflammatory cytokines such as IL-1β, IL-6, and TNF-α inhibits the progression of joint damage in hands and feet in Rheumatoid Arthritis (RA). However, it has been recently reported that TNF inhibitors have little effect on the large weight-bearing joints once joint destruction has started. On the other hand, intraarticular injection of high-molecular-weight sodium Hyaluronate (HA) prevents cartilage degeneration in the large weight-bearing joints in osteoarthritis. Objectives: We examined the effects of combinations of cytokine inhibitor and HA on the expression of ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs), MMPs (matrix metalloproteinases), and RANKL (receptor activator of nuclear factor κB ligand), which all play important roles in joint damage, in human RA fibroblastlike synoviocytes (RA-FLS) and chondrocytes. Methods: RA-FLS and chondrocytes were cultured for 24 h in the presence of synovial fluid from active RA patients (CRP>12 mg/dL, n=5) with or without HA, IL-1 receptor antagonist, soluble TNF receptor-Fc (etanercept), and anti-IL-6 receptor antibody (tocilizumab). After culture, the levels of ADAMTS-4, MMP-3, and RANKL mRNA were measured by real-time PCR. Results: RA synovial fluids induced ADAMTS-4,MMP-3, and RANKL mRNA expressions in RA-FLS and chondrocytes. Cytokine inhibitors partially inhibited ADAMTS-4,MMP-3, and RANKL mRNA expressions, showing that several cytokines are involved in the expression of joint destruction factors. The RA synovial fluids contained IL-1β, IL-6, soluble IL-6 receptor, and TNF-α. HA also partially inhibited ADAMTS-4,MMP-3, and RANKL mRNA expressions. Use of each cytokine inhibitor in combination with HA inhibited the production of these factors further than monotherapy with either. Conclusions: Our results indicate that HA may be useful in preventing joint damage in large weight-bearing joints in RA patients. Furthermore, the concomitant use of cytokine inhibitors and HA might be of greater benefit for preserving cartilage function in RA patients.

Highlights

Rheumatoid Arthritis (RA) is characterized by persistent inflammation of the synovial membranes, and many types of cells are activated by the inflammatory cytokines present in the synovial fluid
Cytokine inhibitors partially inhibited ADAMTS-4,MMP-3, and RANKL mRNA expressions, showing that several cytokines are involved in the expression of joint destruction factors
We examined the effect of RA-SF on mRNA expression of MMP-3, RANKL, and ADAMTS-4 in RA fibroblastlike synoviocytes (RA-FLS) and chondrocytes

Summary

Introduction

Rheumatoid Arthritis (RA) is characterized by persistent inflammation of the synovial membranes, and many types of cells are activated by the inflammatory cytokines present in the synovial fluid. Pro-inflammatory cytokines such as IL-1β, TNF-α and IL-6 play key roles in the pathogenesis of RA. These cytokines are abundant in the synovial fluid of affected joints, and anti-cytokine therapy greatly improves the signs and symptoms of RA [6,7,8] and prevents progression of joint destruction as assessed radio graphically [9,10,11]. Seki et al [12] reported that in all hip and knee joints with moderate to advanced pre-existing damage radiographic progression continued even if patients received TNF-α blockade therapy. Blockade of inflammatory cytokines such as IL-1β, IL-6, and TNF-α inhibits the progression of joint damage in hands and feet in Rheumatoid Arthritis (RA). Intraarticular injection of high-molecular-weight sodium Hyaluronate (HA) prevents cartilage degeneration in the large weight-bearing joints in osteoarthritis

Objectives

Methods

Results